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O P T I C A L A C T I V I T Y D U E T OI S O T O P I C S U B S T I T U T I O N

D is s . L e iden

_ W. C. M. C. KOKKE

1973 nr 18

OPTICAL A C T IV IT Y DUE TOISOTOPIC SUBSTITUTION

PROEFSCHRIFTTER VER KRIJG IN G VAN OE GRAAD VAN DOCTOR

IN DE WISKUNDE EN NATUURWETENSCHAPPEN AANDE R IJK S U N IV E R S IT E IT TE LE ID E N , OP GEZAGVAN DE RECTOR MAGNIFICUS DR. A .E . COHEN,HOOGLERAAR IN DE FA C U LTEIT DER LETTEREN,

VOLGENS B E S LU IT VAN HET COLLEGE VANDEKANEN TE VERDEDIGEN OPDONDERDAG 29 MAART 1 9 7 3

TE KLOKKE 1 6 .1 5 UUR

DOOR

WILHELMUS CHRISTOFFELMARIA C A N IS IU S KOKKE

G e b o re n t e D e l f t i n 19 44

DRUK: K r ip s R e p ro B . V . , M e p p e l

PROMOTOR: PROF. L . J . OOSTERHOFF

CO-REFERENT: PROF. H . WYNBERG

CONTENTS

CHAPTER 1 Introduction 7

CHAPTER 2 16 13( O, 0)-a-Fenchocamphoronequinone 12

CHAPTER 3 1-Deutero-a-fenchocamphoronequinone 38

CHAPTER 4 A comparison of electronic spectra of somenorcamphorquinones 50

CHAPTER 5 Two syntheses of optically pure(1R:2R)-1,2-dimethyIcyclopentane 58

CHAPTER 6 Two methods for the determination ofoptical purity 8g

APPENDIX 16 16Incompleted work on 0- 0-diketones andsuggestions for further work 75

SAMENVATTING 97

ïfioni i

4

Aan mijn Moeder

Ths g re a te r p a r t o f t h i s work has been c a r r ie d o u t unde r th e auspice 's o f

th e N e th e rla n d s F o u n d a tio n f o r Chem ica l Research (S »O .N .) and w ith

f i n a n t i a l a id fro m th e N e th e rla n d s O rg a n iz a tio n f o r th e Advancement o f

Pure Research (Z .W .O .).

16A NATO g ra n t f o r th e pu rchase o f 0 (sha red w i th P ro f . W. P a rk e r

( S t i r l i n g ) and P r o f . G. S na tzke (B onn)) i s g r a t e f u l l y acknow ledged.

The a u th o r a ls o exp resses h is g r a t i tu d e to P r o f . E. H e ilb ro n n e r (B a s e l)18f o r a g i f t o f w a te r , e n r ic h e d in 0 .

6

CHAPTER ONEINTRODUCTION

Historical remarks.Optical activity of organic molecules was discovered early in the 19th

century1. Already in the eighties of that century, the beginning of theflourishing-time of the chemistry of the monoterpBnes,' optical activity wasused for the characterisation of organic compounds.When more monochromatic light sources became available the dependence ofthe angle of rotation on the wavelength could be investigated and anomalousrotatory dispersion curves were discovered. Cotton2 in 1895 was the firstwho measured a circular dichroism curve. From measurements on potassiumchromium tartrate and other coloured substances he concluded that ananomalous rotatory dispersion curve is associated with a CD curve.A satisfactory theoretical evaluation of Cotton effects had to wait untilthe advent of quantum mechanics. In 1928 Rosenfeld gave a quantummechanicaltheory3 on optical activity. In various formulations this theory hasserved as a basis for the explanation of observed effects in CD and ORD.

Study of optical activity due to isotopic substitution became possiblewhen deuterium was discovered in 1932. In 1948 the first example of such acompound of which the specific rotation could be measured, was reported1*(2,3-dideutero-p.-menthane).Many optically active deuterium compounds have been synthesized ever since,either for the study of (biochemical) reaction mechanisms or because theirsynthesis was a challenge^ to a synthetic chemist5. Some examples of optical

1 sactivity dua to O-substitution havs also bssn rsportad^*Measurements of the optical activity of these compounds have never beenused as a basis for theoretical worK^, possibly because no complete Cottoneffect has been reported of this Kind of optically active compounds beforethis work was started.

Scope of this thesis.One might expect that CD of compounds with optical activity due to

Isotopic substitution is especially of interest to theoreticians since themass difference which underlies the optical activity constitutes a smallperturbation of a symmetric situation and- is therefore an attractive

7

problem f o r m athem atical a n a l y s i s .On th e o th e r hand in o b ta in in g s u i t a b l e compounds one i s fac ed w ith a

number o f s y n t h e t i c p roblem s, which have t o be so lved f i r s t . The p re s e n t

t h e s i s i s concerned w ith t h e s y n t h e t i c p a r t o f th e program.

S e le c t i o n o f compounds.The an g le s o f r o t a t i o n due t o hydrogen-deu te rium asymmetry5 are a f a c t o r

500 s m a l le r th a n f o r example th e co rrespond ing e f f e c t s due t o r e p la c in g ahydrogen atom by a methyl group. One may expect a s i m i l a r r e d u c t io n in th e

magnitude o f Known e f f e c t s in CD i f o p t i c a l a c t i v i t y i s due t o i s o t o p i c

s u b s t i t u t i o n on ly .This has consequences f o r th e cho ice o f compounds t o be s y n th e s iz e d w ith

th e purpose o f o b ta in in g CD d a ta :1 / The a b s o rp t io n bands t o be s tu d i e d should have low molar e x t i n c t i o n

c o e f f i c i e n t s ( e . g . e l e c t r i c a l l y fo rb id d e n t r a n s i t i o n s . n->n

t r a n s i t i o n s ] so t h a t c o n c e n t ra te d s o lu t io n s can be used. In o r d e r t o

o b ta in o b se rv a b le CD v a lu e s t h e m agnetic t r a n s i t i o n moment should be -

h igh .2 / The o p t i c a l as w e ll as th e i s o t o p i c a l p u r i t y 8 should be as high as

p o s s i b l e .Requirement 1 / i s f u l l f i l l e d by ca rb o n y l compounds.

Through th e worK o f Deen8 and Emeis^8 on t r a n s -8 -h y d r in d a n o n e [ f i g . 1-13

f i n e - s t r u c t u r e [which i s e s p e c i a l l y pronounced when th e Ketone has a two­

f o ld a x i s ] due t o a p r o g re s s io n o f t h e carbony l s t r e t c h i n g mode in th e'I 8

e x c i t e d s t a t e . T h is p r o g re s s io n i s expected t o change on O - s u b s t i t u t i o n

as w i l l be made c l e a r in th e nex t example.

C ons ider a " s i m p l i f i e d ” o p t i c a l l y a c t iv e Ketone and suppose t h a t only

t r a n s i t i o n s t o one v i b r a t i o n a l l e v e l (and i t s harmonic o v e r tones] o f th e

e x c i t e d s t a t e a re p o s s i b l e , and assume t h i s p a r t i c u l a r mode t o be a group

v ib r a t i o n o f th e ca rbony l group. Then t h i s Ketone should have a very

s im ple CD spectrum : on a frequency s c a le i t should c o n s i s t o f e q u a l ly

d > d>F igu re 1-1

H H

a g r e a t d e a l o f ex p e r ie n c e w ith [mainly] th e'■"V t h e o r e t i c a l f e a t u r e s o f th e ca rbony l group has

been accum ulated in th e Department o f T h e o r e t i c a l

2 O rganic Chemistry in Leiden . One o f th e f e a t u r e s

o f th e ca rbony l a b s o rp t io n a t about 300nm i s th e

6

0-3 0-4

Figure 1-2

0-0

0-6 16 0

0-100-11

0-12J

0-10

T77 kK0-11

0-8

1800-5

0-3 0-4

spaced peaks. Fig 1-2 gives a sketch of this CD spectrum together with that16 18of the antipode where 0 has been replaced by 0. That the progression of

the active mode in the latter compound is smaller (factor /(16/18)) followsfrom the solution of the harmonic oscillator. Thus an equimolar mixture of

18 16these antipodes, one antipodB 100% 0, the other 100% 0, should giverise to an observable CD as the difference of two CD bands with differentcontours.

The CD spectrum of an actual ketone, hydrindanone, is depicted in16 18fig. 1-3. Here also substitution of 0 by 0 would change the progression

of the carbonyl stretch vibration, thus an equimolar mixture of compound 116 18(fig. 1-1) and its antipode 2 where 0 has bBen replaced by °0 should

give rise to an observable effect in CD.In practice it would be very difficult to .obtain both antipodes of a

18ketone of the same opical purity, and to label one antipode with 100% 0.For this reason we directed our attention to the synthesis of dicarbonylcompound with a plane of symmetry in the case both oxygen atoms had equal

18mass, but would lose symmetry if one of the oxygens was replaced by 0(see fig. 7*1 for examples). Our first choice was the synthesis of ana-diketone because of the presence of two absorption bands which are bothaccessible to accurate CD measurements.

9

H

- 30

M n m )

v(10 c m )

FigurB 1-3

General remarks.1/ The situation illustrated in fig. 1-2 is indeed very simplified. The

shift of the frequency of vibrational transitions is not the only causeof an isotopically created CD. There are other origins of such an effectthat will have to be considered in a refined theory such as thBdifferences in amplitudes of vibrations due to different masses of theisotopes, and the influence of anharmonicity of the potentialsgoverning molecular vibrations. The difference in equilibrium bondlength between C-H and C-D as a consequence of anharmonicity, amounts to0.004a only11, but should nevertheless not be neglected.

2/ When we mentioned a plane of symmetry in a dicarbonyl compound withidentical isotopes we included in this term planes of symmetry that areonly present as time-averages, e.g. in the case of rapidly intercon­verting conformers. Introduction of an isotope (deuterium in cyclo-pentanone e.g. 12)) may shift the equilibrium sufficiently to give riseto a measureable optical activity

References.Biot, Bull. Soc. Philomat., (1015) 190.This reference and the next one is taken from: T. Martin Lowry, OpticalRotatory Power, Dover Publications Inc., (1964).

10

2) Cotton, Ann. Chim., {VII} j , 347 (1896).3) L. Rosenfeld, Z. Physik, 32, 161 (1928).**■) E.R. Alexander and A.G. Pinkus, J. Amer. Chem. Soc., 71, 1786 (1949).3) For reviews on H-D asymmetry see:

□. Arigoni and E.L. Eliel, Top. Stereochem., 4, 127 (1969).L. Verbit, Progr. Phys. Org. Chem., _7, 51 (1970).

6) C.J.M. Stirling, J. Chem. Soc., (1963) 5741.M. A. Sabol and K.K. Andersen, J. Amer. Chem. Soc., 91, 3603 (1968).R. Annunziata, M. Cinquinni and C. Colonna, J. Chem. Soc., Perkin

Trans., _1_, 2057 (1972).7) The best example of theoretical work on H-D asymmetry is a paper by

N. V. Cohan and H.F. Hameka (J. Amer. Chem. Soc., 88, 2136 (1966)) onoptically active bromo-chloro-deutero-methane, which has never beenprepared.

®) The isotopical purity is defined as 100x the number of one type ofisotopically substituted molecules, and the total number of moleculesin the mixture (both isotopically substituted and unsubstituted).

9) R. Deen, Thesis Leiden (1961).*®) C.A» Emeis, Thesis Leiden (1968).

Figure 1-3 is taken from this thesis.) Such differences in bond lengths follow from microwave spectroscopicalstudies. Cf. J.E. Wollrab, Rotational Spectra and Molecular Structure,Academic Press, (1967), p 110.

) 3-Deuterocyclopentanone is an example. This compound has been preparedbut no Cotton effect has been detected (C. Djerassi and B. Tursch, J.Amer. Chem. Soc., 83, 4609 (1961)). We recommend reinvestigation of theoptical activity of this compound but with a more sensitive apparatus.Of course, 3,4-dideuterocyclopentanone would be a better choice.

u u u u n u u u u u n n u u u u u u n

11

CHAPTER TWO(160,180)-a-FENCH0CAI<PH0R0NEQUIN0NE

OPTICAL ACTIVITY DIE TO ISOTOPIC SUBSTITUTION. CIRCULAR DICHROISM OFA Q .

(1R)-2- O-ct-FENCHOCAMPHORONEQUINONE1.

Sir:During the last twenty-five years many substances have been synthesized

which derive optical activity from deuterium substitution2. Only a fewexamples of optical activity due to other isotopic substitution havB bBen

1 6 1 0 _ 1 6 1 0reported, viz. some [ 0, 0)-sulphones^ 4 6 and ( 0, 0)-sulphonateesters4. No Cotton effect has been measured in any of these compounds,neither in CD nor in ORD. Two ORD curves only show the first half of aCotton effect6.

in cyclohexane

500nm

(1 R)-2-018- a-fenchocamphoronequinone

Fig. 2-1

We have started the synthesis of a number of diketones which deriveoptical activity from substitution of one 80 by 0. The first compound

1 0which is reported here is an a-diketone: (1R)-2- O-a-fenchocamphorone-quinone (I). The CD-curve between 250 and 520nm has been measured with avery sensitive instrument built by Mr. Dekkers in this department.

12

in iso-octane

5 0 0 nm

500 nm

(IR)-camphorquinone

F ig . 2 -2

in cyclohexane

20 kK

(IS) - isofenchonequinone-0/4

F ig . 2 -3

13

C o rre c te d t o o p t ic a l p u r i t y i t i s d is p la y e d in f i g . 2 -1 to g e th e r w ith th e

a b s o rp tio n c u rv e . Both bands in CD around 280 and 480nm show e x c e p t io n a l ly

pronounced s t r u c tu r e . F o r com parison th e CD and a b s o rp tio n s p e c tra o f

cam phorquinone ( I I ) ( f i g . 2 -2 ) and o f is o fe n c h o n e q u in o n e ( I I I ) ( f i g . 2 -3 )

a re added®. We have n o t y e t measured th e ORD o f compoud I , b u t to g iv e an

id e a o f th e o rd e r o f m agn itude o f th e e f f e c t in ORD, we g iv e in f i g . 2 -4

th e c o n t r ib u t io n t o th e ORD o f th e CD band o f I in th e v is ib le re g io n ,

c a lc u la te d w ith th e a id o f thB K ro n ig -K ra m e rs theorem 9 .

4 0 0 nm

in cyclohexane

(1R)*2*0-- a - fenchocamphoronequinone

R e c e n tly s e v e ra l papers have been p u b lis h e d on th e in te r p r e ta t io n o f

e le c t r o n ic s p e c tra and o p t ic a l a c t i v i t y o f a -d ik e to n e s 11 12. The a s s ig n ­

ment o f e le c t r o n ic t r a n s i t i o n s by some a u th o rs 11 d i f f e r fro m th e a s s ig n ­

ment g iv e n by o th e rs 12. B oth agree in e x p e c t in g th e d ic a rb o n y l group o f I I

t o be tw is te d , b u t th e y d is a g re e in t h e i r p r e d ic t io n o f th e sense o f t w is t .

However, b o th p r e d ic t io n s o f th e sense o f t w is t c o u ld be s u p p o rte d by

argum ents o f c o n fo rm a t io n a l a n a ly s is 13 1‘*.

T h e o re t ic a l a n a ly s is o f th e CD o f compound I , w h ich w i l l be p u b lis h e d

e ls e w h e re , may c o n t r ib u te t o c le a r up th e s e a n t ith e s e s .

NHgO Hr C K C2HBO H rJ ^ N O H I n h 2

(J X ch2

| ru04

f 'IN ^ S e O a r'T'i . H2° 18 f T s'l NH2NH2 rT io1®

^ N N H ,H

^ ^ 0F ig . 2 -5 The s y n th e s is o f compound I fro m (+ ) - (1 S )- fe n c h o n e .

14

D e ta i l s o f th e s y n th e s i s o f I w i l l be p u b l is h e d s e p a r a t e ly by one o f th ea u th o rs (Kokke). A scheme o f th e ro u te fo llow ed i s g iven in f i g . 2 -5 .

R e fe re n c e s .

P a r t o f t h i s work has been p u b l is h e d . See: J . Amer. Chem. S oc . ,

94, 7583 (1972).) For rev iew s on hydrogen-deu te rium asymmetry see :

D. A rigoni and E.L. E l i e l , Top. S te reo c h em . , v o l . 4 , 127.L. V e rb i t , Prog. Phys. Org. Chem., v o l . 7, 51.

3) C.J.M. S t i r l i n g , J . Chem. S o c . , (1963) 5741.

**) M*A. Sabol and K.K. Andersen, J . Amer. Chem. S o c . , 91, 3603 (1968).

5 ) R. A nnunzia ta , M. Cinquinni and C. Colonna, J . Chem. S o c . , P erk in

T r a n s . , 1_, 2057 (1972).6 ) S. E n g la rd , J . S . B r i t t e n and I . L istow sky, J . B io l . Chem.,

242, 2255 (1967).L. V e r b i t , J . Amer. Chem. S o c . , 8£, 167 (1967).

7 ) Data o f t h i s CD-curve. UV band: Aemax=2.4*10 j peaks a t 264.5 , 268.3

275.0 , 279 .8 , 286.7 , 292 .3 , 299 .3 , 306.6 , 314.2 , 322.5 , 331.0

and 3 4 0 .7nm j v i s i b l e band: Aemi =-9.05*10 ; peaks a t 462.5 and4 8 4 .5nm.

8 ) From ORD-measurements o f I I I (H .-P . Gervais and A. R a s sa t , B u l l . Soc.

Chim. F r . , (1961) 745) i t has been c o n c lu d e d ^ ^3a t h a t th e a b s o rp t io n

band around 480nm g iv e s r i s e t o a normal Cotton e f f e c t in CD, whichi s a t v a r ia n c e w ith our r e s u l t s .

) C.A. Emeis, L .J . O o s te rh o f f and Gonda de V r ie s , P roc . Roy. S o c . ,

A 297, 54 (1967).10) The c a l c u l a t e d (max.) am p litude o f t h i s ORD-curve i s 4 2 .2 ° .

11) W. Hug and G. Wagnière, Helv. Chim. A cta . 54, 663 (1971).

W. Hug, J . Kuhn, K .J . S e ib o ld , H. Labhart and G. Wagnière, Helv. Chim.

Acta , 54, 1451 (1971).12) E. Charney and L. T s a i , J . Amer. Chem. S o c . , 93, 7123 (1971).

13) a / A.W. B u r g s ta h le r end N.C. Naik, Helv. Chim. Acta , 54, 2920 (1971).

b / W. Hug and G. Wagnière, Helv. Chim. Acta, J55, 634 (1972).

llf) X-ray a n a ly s i s o f camphorquinone (L. T s a i , E. Charney, J .V . S i l v e r to n

and W.M. B r ig h t , t o be p u b lish ed ) proved th e sense o f t w i s t p r e d ic te d

in 2 ) t o be c o r r e c t ( f i g . 2 - 6 ) . However, /Mils does not mean t h a t thB

assignm ent o f e l e c t r o n i c t r a n s i t i o n s , g iven in 12) , i s a l s o c o r r e c t

15

Fig. 2-6 A model of (-)-(IR)-camphorquinone (II) showing thethe sense of twist as found by X-ray analysis

Mira

(of. chapter 4).15) One of the authors (Kokke) is indebted to the Netherlands Organization

for the Advancement of Pure Research (Z.W.O.) for the sponsoring of1 0this work. A NATO grant for the purchase of 0 is gratefully

acknowledged.W.C.M.C. Kokke15L.J. OosterhoffDept, of Theoretical OrganicChemistry, University of Leiden,P.0. Box 75, Leiden,The Netherlands.

16

A Q

THE SYNTHESIS OF MR)-2- O-a-FENCHOCAMPHORONEQUINONE: SPECIFICLABELING OF ONE CARBONYL GROUP IN A N0RB0RNANE-2,3-DIONE.

W.C.M.C. KoKkeDepartment of Theoretical Organic Chemistry, University of Leiden,

P.O. Box 75, Leiden, The Netherlands.

Summary.A method has been devised for the preparation of a norbornane-2,3-dionewith one of the carbonyl groups enriched specifically in 18o, viz.,oxidation of a labeled ketone with selenium dioxide in acetic anhydride.This method has been applied to the oxidation of labeled, optically activecx-fenchocamphorone giving specifically labeled cx-fenchocamphoronequinone.This diketone, whose optical activity is due only to 180-substitution,showed a small but measureable effect in the CD of both low intensityabsorption bands in the region 250-520nm.

Introduction.Compounds which derive optical activity from isotopic substitution offer

interesting possibilities for studying the origin of vibronic absorptionbands if these bands are accessible to CD-measurements. Up to now much workhas been done to synthesize compounds whose optical activity stems fromdeuterium substitution16. In addition a few examples have been reportedwhere optical activity is due to oxygen isotopes, viz. some

0- 0-sulphones17 18 19 and 160-180-sulphonate esters18.Measurement of the optical activity of these compounds has usually resultedin plain ORD-curves20.

In view of this situation it seemed worth while to start a program for•the synthesis of ketones and diketones with optical activity due toisotopic substitution. a-Diketones were particularly inviting because twolow intensity absorption bands in the region 25G-520nm can be studied by CDprovided the effect is large enough.

One of our efforts was directed towards the synthesis of a specifically,labeled 0- 0-<x-diketone starting from optically active norcamphor ora-fenchocamphorone C_5). Because of the availability and the price of

16starting materials (H2 0 e.g.) it was decided to try out the various stepsin the synthesis with cheaper materials. This resulted in a number ofinteresting observations which will bB discussed first.

17

Model experiments.Initially the synthesis of specifically labeled camphorquinone was'

18 1Ö 2 1attempted from camphor. Water, enriched in 0 (2.095 at.% 0 zl)3 wasfj gused for labeling the reagents, since an 0-label of 2% is sufficient highto detect the possible exchange of oxygen between the reagents and thereaction medium by mass spectroscopy.

Figure 2-7+ Se02 + Se + H2O

An a-diketone is most conveniently prepared by oxidation of a ketonewith selenium dioxide22. Because the water formed in this reaction(fig. 2-7) reacts with selenium dioxide to form selenious acid, whichmight catalyse in unfavourable conditions exchange of oxygen between thecarbonyl group and water23, a solvent was required in which eitherselenious acid was insoluble, or the water formed could be removed.

In a first experiment labeled camphor was oxidized with selenium dioxidein acetic anhydride21* (molar ratio of camphor, selenium dioxide and aceticanhydride =0.33 : 0.54 : 0.53), the intention being to bind the waterformed with acetic anhydride. This first experiment was a faillure: the

18camphorquinone prepared from labeled camphor (2.26% 0) had too low aA Q 'l Q

label (1.52% 0; retention is 2.45% 0).Various passible reasons for this loss of label were systematically

investigated. First it was verified that labeled camphor does not loselabel2 5 when boiled with acetic anhydride for four hours26Similarly no loss of label occurred when 0.3g of water was added to aboiling solution of 2.5g of labeled camphor in 2.5ml of acetic anhydride(molar ratio of camphor, water and acetic anhydride = 0.33 : 0.33 : 0.53).Apparently under these conditions the reaction between water and aceticanhydride is much faster than the acetic acid-catalyzed exchange reactionbetween water and camphor.

Reconsidering in the light of these results the oxidation experiment inwhich loss of label did occur, it was realized that both ketone andsolvent29 were oxidized by selenium dioxide so that toward the end of thereaction hardly any acetic anhydride was left. The lifetime of a watermolecule then became long enough to permit oxygen exchange with thecarbonyl group.

Indeed it was found that loss of 1B0 in the oxidation of labeled camphor

18

can be prevented by sufficiently reducing the quantity of selenium dioxidewith respect to camphor and acetic anhydride. Although the mass spectra ofcamphorquinone clearly showed retention of label2 6 and that selective labelincorporation had been achieved30, the possibility of interchange of thetwo oxygen atoms within one diketone molecule could not be excluded on thebasis of these results ■ On the other hand this process seemed to be veryimprobable so that continuation of the synthesis with highly labeledmaterials seemed justified.

Meanwhile two other routes to the desired compounds had been explored.It appeared that the oxidation of labeled camphor with selenium dioxide intoluene proceeds with retention of label, although in poor yield. In thiscase water is probably removed by the excess of unreacted selenium dioxide.Finally it was tried to devise an oxidation reaction for the preparation ofcamphorquinone where water could not possibly be a reaction product, sothat troubles due to exchange with water could not occur. The oxidation ofcamphor-enol-benzoate was attempted with selenium dioxide in benzene.Camphorquinone and benzoic acid were formed in good yield. However, whenlabeled selenium dioxide was employed, randomly labeled camphorquinonewas obtained.

Experiments with high label incorporation.

Fig. 2-8

CH^

The synthesis of the title compound (8] from( + )-(1S]-fenchone. (Absolute configurations are depicted3**.)

18The route followed to (1R)-2- O-a-fenchocamphoronequinone (8) isindicated in fig. 2-8.

The required a-fenchocamphorone t5) was prepared via a-fBnchene (4) fromfenchone ; this route was chosen because it was judged to be the one bywhich a-fenchene (4) of the highest chemical purity could beobtained3 s 3B. The a-fenchocamphorone (5J thus obtained did not contain

19

th e most l i k e l y im p u r it y (5-fenchocam phorone [1 0 ] , because a f t e r se le n iu m

d io x id e o x id a t io n th e d ik e to n e o b ta in e d was o p t ic a l l y in a c t iv e (no e f f e c t

in CD), i . e . th e d ik e to n e d id n o t c o n ta in a m easureable q u a n t i ty o f

(5-fenchocam phoronequinone (_11_) as an im p u r it y 8.

a-Fenchocam phorone (5 ) was la b e le d by re g e n e ra t io n fro m th e hydrazone18 18

(6 ) w ith w a te r e n r ic h e d in 0 . T h is la b e le d ke tone c o n ta in e d 62.72% □.

A f t e r th e o x id a t io n w ith se le n iu m d io x id e in a c e t ic a n h y d rid e some18

u n re a c te d ke tone was re c o v e re d w ith a la b e l o f 60.19% 0} o f th e d ik e to n e18p re p a re d 48.05% was s p e c i f i c a l l y la b e le d w ith 0 , and 0.08% was do ub ly

la b e le d . C o m p le te ly s p e c i f ic la b e l in g had been a ch ie ved 9 .

Much le s s la b e l i s m is s in g fro m th e ke tone re c o v e re d th a n fro m th e

d ik e to n e fo rm ed . One m ig h t suppose t h a t oxygen exchange o f th e d ik e to n e

w ith w a te r fo rm ed d u r in g th e se le n iu m d io x id e o x id a t io n i s f a s t e r tha n

oxygen exchange o f th e s t a r t in g m ono-ke tone . The r e s u l t s o f two exchange

e x p e rim e n ts c o n firm e d t h is h y p o th e s is .

- A homogeneous s o lu t io n o f a -fenchocam phorone (0 .5 7 5 4 g ), a - fe n c h o -18

cam phoronequinone (0 .5 3 6 3 g ), la b e le d w a te r (1 .1 2 1 0 g , 12 .062 a t.-s D ) )

and 0.20N a c e t ic a c id in d ioxa ne (1 .1 2 3 0 g ) was l e f t a t room te m p e ra tu re f o r

96 h o u rs . A f t e r w o rk in g -u p i t was shown th a t th e ke tone had h a rd ly1 fi 18

exchanged oxygen ( la b e l 0.38% 0) no la b e l i s 0.2% 0 ) , whereas 14.90-s18

o f th e d ik e to n e was la b e le d w ith one 0.

- La be led a -fenchocam phorone and a-fenchocam phoronequ inone were d is s o lv e d

in a c e t ic a n h y d r id e and to th e b o i l i n g s o lu t io n th e q u a n t i ty o f w a te r

c a lc u la te d to h y d ro ly s e th e a n h y d r id e was g ra d u a lly added. Both ke tone andb Q

d ik e to n e lo s t la b e l , b u t th e d ik e to n e much f a s t e r th a n th e ke tone .

O p t ic a l p u r i t y .

Our s t a r t in g fen chon e-o x im e 12) had [a }p + 4 1 .1 9 ta b s . EtOH): com parison

w ith a r e l ia b le v a lu e o f [a ]p + 4 6 .5 ° (E tO H )118 in d ic a te s an o p t ic a l p u r i t y

o f 88.6%.The p h y s ic a l c o n s ta n ts re c o rd e d by R a ssa t* 1 * * * **7 f o r ( IS )-a -fe n o h o ca m p h o ro n e :

Tal -6 0 ° (E tO H ), A e -1 .6 0 (c y c lo h e x a n e ), a re n o t c o n s is te n t w i th o u r b e s tL J D max cd a ta : ra L + 6 7 .0 5 ° (NeOH)“ 8 , A e + 2 .3 (c y c lo h e x a n e ). M a tt in e n re co rd e d

l J y max[a ] + 73 .9 4 ° (EtOH) > i f t h i s i s ta ke n as th e c o r r e c t v a lu e , th e n o u r

a -fenchocam phorone has an o p t ic a l p u r i t y o f 90.7%.16 18

A d is c u s s io n o f th e o p t ic a l p u r i t y o f th e 0 - 0 -d ik e to n e p re pa red

20

Se--O*

Fig. 2-9 A mechanism which gives rise to specifically labeleddiketone, but with partial racemisation.

according to fig. 2-0 must involve the mechanism of the oxidation reactionwith selenium dioxide. Corey and Schaefer1*9 have postulated a selenite-enol-ester as a reaction intermediate. If such a species is formed via acyclo-addition of selenium dioxide to the ketone, then one would expectCfig. 2-9) in our case 66.67% racemisation and 25% loss of label. Thismechanism seems unlikely because labeled camphor can be oxidized withretention of label 5 and our exchange experiments suggest, that duringthe oxidation of a-fenchocamphorone loss of label is due to exchange withwater.

If we assume that oxidation of labeled Ot-fenchocamphorone with seleniumdioxide gives rise to no racemisation because of the mechanism of theoxidation reaction50, then (1R)-2- ^O-a-fenchocamphoronequinone (0) hasan optical purity of 90.7%.

Spectra.Measurement of the CD of specifically labeled a-fenchocamphoronequinone,although very small, proved to be possible. This spectrum (fig. 2-1) hasalready been published 51 5 2. The influence of 1fl0-substitution (label

1862.72% 0) on the CD of a-fenchocamphrone was only small. In fig. 2-10 theratio A/B of thB values of Ae in the two maxima would be 1% higher if theCD of the labeled ketone was depicted here instead of the CD of theunlabeled ketone. The dotted line in fig. 2-10 encloses a part of the graphwhich is different in the case of the labeled ketone. In fig. 2-11 thisdetail of the CD curves of both labeled and unlabeled ketone is enlarged.The influence of ^-substitution on the absorption spectra of ketone (7)and diketone (_0) could not be detected with a Cary-14 or a Cary-15.

21

in cyclohexane

(1R) - a - fenchocamphorone(unlabeled )

Figure 2-10 CD of compound S_.

Figure 2-11 Detail of the CD oflabeled (C) and unlabeled CD)a-fenchocamphorone (in cyclohexane)

AE =1.8

AE = 1.0320 nm

Model experiments not involving use of selenium dioxide.Simultaneously with the oxidation of a Ketone and an enol-ester withselenium dioxide, some other reactions which might led to specificallylabeled diketones were investigated as well. These model experiments, notinvolving use of selenium dioxide, are described in this section,1/ Ruthenium tetroxide is a vigorous oxidizing agent which reacts with

carbon-carbon double bonds to give carbonyl functions. It is used inanalytical chemistry to determine the number of double bonds in steroids53). We found that ruthenium tetroxide reacts with a-methylene-camphorto give camphorquinone, However, we have not investigated whetheroxidation of ^0-a-methylene-camphor with this oxidizing agent proceedswith retention of label55.

22

2/ It was found that O-a-methylene-camphor can be ozonised to givecamphorquinone with about 30% loss of label56.

3/ The synthesis of a-hydroxy-camphor-acetate was attempted by reactinga-bromo-camphor with silver acetate. Camphorquinone might have beenprepared from a-hydroxy-camphor-acetate in two steps and in fair yield,cf. fig. 2-12.

Figure 2-12

But siver acetate abstracted hydrogen bromide from a-bromo-camphor anda reaction product C ^ H ^ O was formed. We have not investigated thestructure of this product57 56. Because 2-hydroxy-3-bromo-camphane is.reported not to be stable66 we have not tried to react this compoundwith silver acetate.

4/ One of the methods for the methylation of amines is heating the aminewith formalin and acid (the Leuckart reaction)63, However, when a-amino-camphor-hydrochloride is treated with formalin, the expectedN-methylated product is not isolated, but camphorquinone instead62 63.We have examined the possible utility of the Leuckart reaction for ourpurpose by heating in a sealed tube a-amino-camphor-hydrochloride,labeled water and 1/3-dioxolane. In this manner in situ labeledformaldehyde could be generated, because it is known, that on hydrolysisof an acetal the oxygen of the carbonyl group formed is provided by thewater66. After the reaction it appeared , that the liquid from whichcamphorquinone was filtered, was acid and accordingly the camphorquinoneisolated had to high a label because exchange had occurred between thereaction product and the excess of labeled water.We have obtained except for camphorquinone a colourless compound^11^16^2 reaction. The structure of this compound has not beenelucidated.

5/ One of the latest developments in the organic chemistry of thallium isthe discovery65 that oximes can be hydrolysed by T1(N03)3-3H 0 inbenzene. It was hoped that isonitrosocamphor (=camphorquinone-3-oxime),labeled by exchange, might be converted in specifically labeled camphor­quinone. However, reaction of thallium trinitrate with isonitrosocamphorgave rise to a range of products, each in low yield.

23

Experimental.Melting points are not corrected. Angles of rotation were determined with aBendix-NPL photoelectric polarimeter at room temperature.Mass spectra. Labels were calculated from peak intensities in spectraobtained with a MS-9 mass spectrometer. Because of the various methods tocalculate percentage labeling from peak intensities, we give a numericalexample of the method we have used. In the mas.s spectrum of a sample oflabeled camphorquinone peaks due to molecular ions are atM/e=166,167,168 with rel. intensities 100 : 11.19 : 2.275. Correction ofthe peak intensities for M/e=167,168 for satellites of M/e=166 due to 0 and13C is done by comparison with a mass spectrum of C^QH^. Rel. peakintensities for M/e134,135,136 in 100 : 11.03 : 0.55 66).1eo-labal=((2.275-0.55)/(100+(11.19-11.03)+(2.275-0.55)))x100%=1.67% 0.Note, the absolute 0 content is calculated; no correction for naturalabundance is applied.

oCamphor-hydrazone67 was recrystallised from iso-octane. Stored at -20 overP 0 it did not liquefy as observed in 67), and after a year the crystals2 5had only turned slightly yellowish.Camphor-enol-benzoate, prepared according to 68), appeared to be veryimpure (G.L.C.). The composition of the reaction product depends on thereaction time: when camphor is refluxed with benzoyl chloride during 4hours, the enol-ester is the main product, but when refluxed overnightanother component of the mixture (probably the benzoate of 1-hydroxy-camphene) becomes the main product. The enol-ester was purified by columnchromatography over silica gel. Elution with carbon tetrachloride then gavepure camphor-enol-benzoate. The enol-ester is a liquid at room temperature.NMR data (CC1.) (shifts with respect to TMS): three methyl groups at6=0.791, 0.886, 1.042ppm; H attached to C (bridge-head proton): triplet,6=2.831ppm, J =2x3.50Hzs H attached to C (vinylic proton): doublet,6=5.742ppm, J=3.68Hz.Labeling of camphor by hydrolysis of camphor-hydrazone. A mixture ofcamphor-hydrazone (8.3g), labeled water (3.6ml, 2.095 at.'S 0 )) andethylene chloride (50ml) was placed in a heavy walled, long necked flask ata high vacuum line, degassed, and hydrogen bromide (1.67l/20°/1atm.) wasthen frozen into it. The sealed mixture was left overnight, then heatedwhilst magnetically stirring for 8 hours at 80°. Normal isolationprocedures then gave the labeled camphor which was purified twice by

24

*1 Bs u b lim a t io n to g iv e 6 .0 g o f cam phor, la b e l 2.26% 0.

L a b e lin g o f se le n iu m d io x id e by exchange. H ig h ly la b e le d se le n iu m d io x id e

was p re p a re d by exchange between se le n iu m d io x id e (4 .9 g ) and la b e le d18

w a te r M .O g , 91.8% 0 , a g i f t o f P r o f . E. H e ilb ro n n e r , B a s e l) (16 hou rs on

a ba th a t 130 J . 'T h e w a te r was th e n removed w ith a r o ta to r y e v a p o ra to r

u n t i l th e re s id u e c r y s t a l l i s e d . D ry in g was e f fe c te d in an oven o v e r P^O in

vacuo. Labe l c a lc u la te d on th e b a s is o f com p le te exchange 31.25% 180.

O x id a t io n s o f la b e le d cam phor. Two s e le c te d e x p e r im e n ts ,1 B

- A m ix tu re o f la b e le d camphor (3 .0 g , 2.19% 0 ) , se le n iu m d io x id e (T .5 g )

and a c e t ic a n h y d r id e (3m l) was heated f o r th re e hours a t 145°. A f te r

rem ova l o f th e s o lv e n t and s u b lim a t io n th e c rude p ro d u c t (1 .8 g ) was

se p a ra te d by p re p . G .L .C . to g iv e camphor (0 .8 g ) and cam phorquinone (0 .5 g ,1 8 4 Q

la b e l 2.27% 0 ) . R e te n t io n o f la b e l i s 2.36% 0.1 B

- A m ix tu re o f la b e le d camphor (2 .5 g , 2.19% 0 ) , se le n iu m d io x id e (1 .8 5 g )

and d ry to lu e n e (5m l) was r e f lu x e d f o r 15 .5 h o u rs , th e n th e s o lv e n t was

removed and th e re s id u e s u b lim e d . S e p a ra tio n o f th e c rude m ix tu re (2 .0 g )

gave camphor (1 .4 g ) and cam phorquinone ( 0 .1 g ) , la b e l 2.32% 1S0 . R e te n t io n

o f la b e l i s 2.36% 1SQ.

O x id a t io n o f cam p ho r-e n o l-b e n zo a te w ith la b e le d s e le n iu m d io x id e . A s t i r r e d

m ix tu re o f benzene (9 m l) , la b e le d s e le n iu m d io x id e (3 .0 g , 31.25% 1S0) and

ca m p h o r-e n o l-b e n zo a te (4 .4 g ) was hea ted a t 150-160° in an a u to c la v e f o r

3 .3 h o u rs . (The re a c t io n can be c a r r ie d o u t in x y le n e as w e l l (4 h o u rs ,

r e f lu x ) , b u t we chose benzene because i t can be removed more e a s i ly . )

M ethylene c h lo r id e was the n added to th e coo le d r e a c t io n m ix tu re w h ich was

f i l t e r e d . B en zo ic a c id was removed by w ash ing w ith NaHC03 s o lu t io n . A f te r

s u b lim a t io n th e cam phorquinone was p u r i f ie d by r e c r y s t a l l i s a t i o n (2 x ) from

c yc lo h e xa n e ; th e m othe r l iq u o r s were w orked-up by p re p . G .L .C . (SE-30

co lum n ). Y ie ld 2 .0 g ; 30.95% o f th e m o le cu le s was la b e le d w ith one ^ 80,

3.58% was do u b ly la b e le d ; th e fra g m e n t (M-C0) had a la b e l o f 19.00% ”*8016

( 3 2 .5eV s p e c tru m ], 19.07% 0 (15eV s p e c tru m ). These d a ta seem c o n s is te n t18 18

w ith a d ik e to n e , la b e l 19.14% 0 , th e 0 random ly d is t r ib u te d o v e r th e

c a rb o n y l g ro u p s : v i z . , expec ted f o r t h i s case 30.95% o f th e m o lecu les18

la b e le d w ith one 0 , 3.66% d o u b ly la b e le d , a fra g m e n t (M-C0) w ith a la b e l

o f~ 1 9 r1 4 v jfl0.18We s h o u ld e xp e c t a random d i s t r i b u t i o n o f 0 o v e r th e c a rb o n y l g roups o n ly

i f bo th oxygen atoms o f th e d iR e to ne form ed were p ro v id e d by se le n iu m

d io x id e . B ut th e la b e l o f th e d ik e to n e i s abou t 2 /3 o f th e v a lu e w h ich t h is

25

mechanism would suggest (19.14% instead Of 31.25% 0)j this loss of labelmight be due to exchange prior to oxidation.

According to our measurements, when optically pure camphor is used forthe preparation of the enol-benzoate, then oxidation of this enol-benzoategives optically pure camphorquinone.(+]-Fenchone-oxime (2) was prepared from (+)-fenchone (Fluka, purum)according to Wallach69 in at least 80% yield. -[a]D+41.19° (abs. EtOH),mp 162-4° after recrystallisation from heptane and dilute alcohol. Lit.9 :[a] +46.5° (EtOH). mp 167°.Fenchylamine (3) was prepared from 2_ by reduction70 with sodium andalcohol. The hydrochloride after two recrystallisations from dioxane had aspecific rotation of £aj -4.53° (MeOH).(-)-a-Fenchene (4). The amine 3 was regenerated from the hydrochloride andtreated with nitrous acid71. The reaction products were separated byfractional distillation using a Nester-Faust spinning band column (^20cmHg). From 1.5kg of 1 86g of a-fenchene fractions was obtained (purity>87.4%) that were used for the preparation of a-fenchocamphorone (5,3. Forthe measurements more pure 4 was obtained by careful redistillation (^20cmHg, 2ml/hour) of a fore run. The purest sample (99.54%) had Qx]D*42.62(ethyl acetate).(+)-a-Fenchocamphorone (_5) • Some early terpene chemists72 have prepared ^by ozonisation of 4. but Mattinen35° failed to reproduce their reasonableyields. We prepared 5 by oxidation of 4_ with ruthenium tetroxide inmethylene 'chloride in 65.5% yield. A sample of the crude ketone wassublimed: then mp 91-6°, [a]D+57.93° (MeOH) was found. Another sample wasoxidized with selenium dioxide21*, and after distillation the oxidationproduct was purified by prep. G.L.C. (SE-30 column) in order to removeunreacted ketone. After sublimation the a-fenchocamphoronequinone had mp139.0-9.5°. No effect in CD could be detected. Therefore 5 was notcontaminated with g-fenchocamphorone (10), because it would have beenpossible to detect g-fenchocamphoronequinone (Vl_) by CD38.[-)-ct-Fenchocamphorone-hydrazone (_6) was prepared from _5 in the manner of67) in 74.4-82.2% yield. 6 was a liquid at room temperature, butcrystallised on storing at -15°. Different angles of rotation were recordedfor two preparations: [cQ q-51.27 and -58.32 (MeOH).Hydrolysis of 6, introduction of the label.- Labeling procedure. In a degassed mixture of _6, labeled water and

18

26

ethylene chloride, attached to a highvacuum line, HBr was introduced. Themethod used is the same as waspursued for the labeling of camphorby hydrolysis of its hydrazone. But itwas found more convenient to introduceHBr in the reaction mixture using abreak-seal vessel. A break- sealvessel with two taps and a groundglass joint [see fig. 2-13) wasflushed with HBr, the lower part ofthe vessel was then immersed in liquidnitrogen and the calculated quantityof HBr C2 moles of HBr : 1 mole ofhydrazone) admitted and condensed. Thetaps were melted off. The the vesselwas attached to the high vacuum line,the seal was broken, the liquidnitrogen removed, and HBr frozen into the reaction mixture. Because of the

A Q

high price of water, highly enriched in 0, the excess of water for thehydrolysis of must be as small as possible. As already described we used4g of water for the hydrolysis of 8.3g of camphor-hydrazone, and weobtained 6.0g of camphor and 2.0g of residue (azine).It might be expected that further reduction of the quantity of water withrespect to the hydrazone would result in an increase of the yield of azine.In the case of £ azine formation is sterically more easy than in the caseof camphor-hydrazone. Thus when 8.3g of camphor-hydrazone was hydrolysedwith 2.0g of water, 4.4g of camphor and 3.2g of residue was obtained, but£ (7.6g), hydrolysed with water (2.0g) in ethylene chloride C50ml) gave4.4g of residue and 2.65g of Si, mp 100-5°, [a]D+65.10° CMeOH).- Labeling. Water containing 0.31 at.% 17Q, 62.88 at.% 180 and 64.0 at.% □2 1 . A Q

) was used. We used dButerated water, enriched in 0, because it is less16expensive than water, enriched in 0, where the deuterium content has been

reduced to natural abundance. Thus _5 will be labeled with 1S0 anddeuterated, but only in the 3-position. Deuteration of norbornanones iswell documented73. Introduction of D at the exo-3-position is easy,introduction of a second □ is more difficult, and deuteration at the

Figure 2-13

27

6 - p o s i t io n does n o t ta k e p la c e under o u r c o n d it io n s .

6 (7 .6 g ) was h y d ro ly s e d w ith la b e le d w a te r (2 .0 g ) and HBrj 7_ (2 .4 5 g ) was

o b ta in e d and 4 .75g o f re s id u e o f s u b lim a t io n . La be ls were c a lc u la te d in th e

assum ption th a t o n ly m o n o -d e u te ra tio n had o c c u rre d . S p e c i f ic 3 -d e u te ra t io nA Q

3.25%. la b e l 62.72% 0 .

S p e c i f ic a l ly la b e le d a -fenchocam phoronequ inone .' ^ Q

- H igh la b e l in c o r p o r a t io n . 7_ (2 .4 0 g , 62.72% 0) was hea ted w ith se len ium

d io x id e (1 .5 3 g ) and a c e t ic a n h y d r id e ( 2 . 2m l] (4 hours on a b a th a t 15D ) .

U s ing 20ml o f d ry m ethy lene c h lo r id e th e re a c t io n p ro d u c t was s e p a ra te d

fro m se le n iu m by f i l t r a t i o n , washed w ith b ic a rb o n a te s o lu t io n t i l l n e u t r a l ,

th e n w ith a s a tu ra te d NaCl s o lu t io n . The s o lv e n t was removed w i th s u c t io n

and th e re s id u e d i s t i l l e d . D ik e to n e and u n re a c te d monoketone were s e p a ra te do

by p re p . G .L .C . (SE-30 co lu m n ). 0 .88g o f 7 was re c o v e re d , mp 106-10 ,A 0

s p e c i f ic 3 -d e u te ra t io n 3.44%. la b e l 60.19% Oj 0 .5 5g o f 8 was o b ta in e d ,18

48.05% o f t h is d ik e to n e was la b e le d s p e c i f i c a l l y w i th 0 , 50.87% wasA g

u n la b e le d , and 0.08% do ub ly la b e le d w i th 0 . A s o lu t io n o f j8 showed CD in

b o th a b s o rp t io n bands between 250 and 520nm. That th e observed CD in th e

v is i b le re g io n was due to is o to p ic s u b s t i t u t io n c o u ld n o t be c a l le d in -

q u e s t io n because th e p re c u rs o r T_ does n o t absorb th e re , b u t i t happens to

be t h a t th e second a b s o rp tio n band o f J3 a t abou t 300nm c o in c id e s w ith an

a b s o rp tio n band o f th e p re c u rs o r 7_, th u s i t had to be made su re th a t th e

observed CD o f 8 a t abou t 300nm was indeed due to jJ and n o t due to th e

p re c u rs o r . The CD band we observed in t h is re g io n was shaped l i k e th e CD

band o f 7 , b u t i t had a v e ry unusua l f in e s t r u c tu r e . Because o f t h i s band

shape and i t s p la c e we had a shrewd s u s p ic io n t h a t t ra c e s o f 7_ in te r fe r e d

w ith th e CD measurem ent. Indeed we showed _8 by G .L .C . to be con tam in a ted

w i th 0 .1 -0 .2 % o f 7 , T h is im p u r it y was removed by p re p . G .L .C . to y ie ld j j

( 0 . 4 g ) , mp 1 4 0 .0 -0 .5 ° . Then CD was measured a g a in ; th e th e n observed CD

o f j i i s d is p la y e d in f i g . 2 -1 .

- The u l t im a te p ro o f th a t th e observed CD o f j i i s due o n ly to is o to p ic

s u b s t i t u t io n is an exchange e x p e r im e n t. F i r s t CD and a b s o rp tio n was

measured o f a s p e c tro s c o p ic s o lu t io n o f B (24.2m g) in heptane (1 0 m l). Then

to t h i s s o lu t io n was added w a te r (4g) and a c e t ic a c id (1 g ) ; t h i s m ix tu re

was m a g n e tic a lly s t i r r e d a t room te m p e ra tu re f o r 15 .25 h o u rs , n e u t r a l is e d ,

thB la y e rs were s e p a ra te d , th e hyd roca rbon la y e r d r ie d and used f o r th e

measurement o f CD and a b s o rp t io n . No CD c o u ld be d e te c te d , w h ich se rve s

as a p ro o f f o r th e p u r i t y o f th e o p t ic a l d e n s ity in th e v is i b le re g io n

28

decreased by ^50% during the experiment. This might be due to theformation of a hydrate1*3.

Experiment with labeled selenium dioxide and unlabeled Ketone: attemptedpreparation of (1S)-2- O-a-fenchocamphoronequinone, the antipode of 0.Using labeled selenium dioxide (31.25% 180) and 5. and conditions as in the

18experiment with highly labeled 7_, O-a-fenchocamphoronequinone wasobtained. Some unreacted Ketone (label 0.86% ^G) was recovered. Of the

i 8diketone was 10.62% labeled with one 0 and 0.27% was doubly labeled. Ifno exchange between selenium dioxide and the reaction medium had occurred,we should expect 31.25% of thB diketone to bB specifically labeled. Becauseof the low label the effect in CD of this diketone should be very weak, butthe two highest peaks in the visible band (see fig. 2-1) should have beenabove noise level. (The max. pen deflection expected in CD on the basis ofthe optical density of the solution of the diketone, its low isotopicalpurity (10.62%) and the observed CD of j) (fig. 2-1) was 9mmj the noiselevel of the CD apparatus was 3mm.) However, no CD could be detected.Presumably partial racemisation had occurred.Exchange experiment with 7 and 6 (both labeled by exchange) in Ac 0.A solution of 7_ (0.4329g) and 8 (0.4013g) in acetic anhydride (2.1g) washeated under reflux. Water was added with a syringe in 5yl portions atintervals of three minutes. After addition of 30% of the calculatedquantity of water (=30% of 0.37g) a sample of the mixture was taken for thedetermination of the labels: sampling was also done when 50, 70 and 90% ofthe water had been added. The results are shown in the table.

water added, % diketone, labeled18with one 0, %

i Aketone, % 0

0 19.24 30.230 13.70 29.450 11.25 28.970 7.31 27.490 5.84 26.3

q-Nethylene-camphor cam be prepared after Dallacker7** and after Snatzke75.a-Methylene-norcamphor is best prepared by means of a Mannich reaction76:Alder77 has described a more complicated synthesis of this compound.Substituted a-methylene-camphors such as a-isopropylidene-camphor can beprepared by reaction of the Grignard reagent of a-bromo-camphor withaldehydes and ketones, followed by dehydratation76.

29

a-Methylene-camphor, labeling by exchange. A mixture of ot-methylene-camphorA Q

(5g), labeled water (15g, 2.D95 at.% 0 21)), THF (20ml) and p.-toluene-sulphonic acid (0.5g) is refluxed for 23.5 hours. The layers are separated,the aqueous layer is extracted once with pentane (5ml). The combinedorganic layer and pentane extract then are washed with water, dried and

A gdistilled. Yield 3.8g, label 2.0 % 0.Attempted synthesis of q-hydroxy-camphor-acetate. After refluxing overnighta mixture of a-bromo-camphor (10g) and silver acetate (7.9gs freshlyprepared) in chloroform (100ml) no appreciable reaction had occurred.Therefore a solvent was used that permitted a higher reaction temperature.The same quantities of silver acetate and a-bromo-camphor in DMSO (100ml)were heated at 150° whilst magnetically stirring for 15 hours. From G.L.-C.-measurements (SE-30 column) it was then deduced that reaction had occurred,only products were formed with a retention time shorter than the startingmaterial. Mol. ratio of the only important reaction product and thestarting material about 17:42. The reaction product was analysed asC H 0. The same product was formed when a-bromo-camphor was refluxBd with10 14silver acetate in pyridine.a-Amino-camphor-hydrochloride. Isonitrosocamphor79 was reduced with zincand base to give a-amino-camphor80. The hydrochloride was prepared bysaturating an ethereal solution of the amine with hydrogen chloride. Thenthe ether was.removed and the hydrochloride recrystallised from absolutealcohol : dioxane 1:1.The Leuckart reaction. In a Carius tube was placed 0.5g of a-amino-camphor-hydrochloride. 0.69g of 1,3-dioxolane and 0.58g of labeled water (2.095at.% 160 21)). The tube was evacuated, sealed, and heated in an oil bath at145° for two hours. After cooling the crystals were removed by filtration.The filtrate was a brown liquid, pH* 2-3 (indicator paper). Onrecrystallisation of the dried crystals from hexane (3ml) camphorquinone

i 3was obtained (75mg, fine needles), label 4.44% 0. Retention of label is2.28% 1S0. On standing the hexane of the mother liquor graduallyevaporated and colourless crystals of a compound were formed. Theabove reaction was repeated on a larger scale, part of the camphorquinonewas removed by crystallisation and the mixture of the unknown compound'andcamphorquinone separated by prep. G.L.C. (Apiezon, 220 ) 81). Starting with6.5g of a-amino-camphor-hydrochloride there was obtained 0.75g of theunknown compound, mp 80-5° from hexane. This compound was not identified.

30

Acknowledgement.The author is indebted to the Netherlands Organization for the Advancementof Pure Research (Z.W.O.) for the sponsoring of this work. A NATO grant forthe purchase of 0 is gratefully acknowledged. It is with pleasure thatthe author expresses his gratitude to Dr. N.C. Rol (Shell Research N.V.,Amsterdam) and to Drs. Klebe, Van Thuyi and Mr. J.J. van Houte in thislaboratory, who spent a great deal of time on the measurement of **®o-1abels, to Prof. W. Parker (Stirling) and to Prof. H. Wynberg (Groningen)for their help in improving the presentation of this paper, and to Prof.E. Heilbronner (Basel) whose gift of labeled water enabled us to do someexperiments with highly labeled selenium dioxide. This work was done inthe department of Prof. L.J. Oosterhoff.

References.) For references on hydrogBn~deuterium asymmetry see:G. Arigoni and E.L. Eliel, Top. Stereochem., vol. 4, 127.L. Verbit, Progr. Phys. Org. ChBm., vol. 7, 51.

7) C.J.M. Stirling,-J. Chem. Soc., 5741 (1963).) (I.A. Sabol and K.K. Andersen, J. Amer. Chem. Soc., 91, 3603 (1968).

®) R. Annunziata, M. Cinquinni and C. Colonne, J. Chem. Soc., PerkinTrans.» 2057 (1972).

) Only two exceptions are known (H~D asymmetry), cf.- s- Englard, J.S. Britten and I. Listowski, J. Biol. Chem.,

242, 2255 (1967).L. Verbit, J. Amer. Chem. Soc., 69, 167 (1967).

) Determined by Miles Laboratories Inc..) For references to the literature on the application of selenium dioxidein organic chemistry, seeFieser & Fieser. Reagents for Organic Synthesis, Wiley-Interscience.

vol. 1, 992i vol. 2, 360j vol. 3, 245.S. Patai, ed.. The Chemistry of the Carbonyl Group, Interscience

Publishers, vol. 1, 159 (1966).R.L. Augustine, ed.. Oxidation, Marcel Oekker Inc., vol. 1, 119 (1969).

) M. Byrn and M. Calvin, J. Amer. Chem. Soc., 86, 1916 (1966).P. Greenzaid, Z. Luz and D. Samuel, Trans. Farad. Soc,, 2787 (1968).

) W.C. Evans, J.M. Ridgion and J.L. Simonsen, J. Chem. Soc., 137 (1934).2S) In the low label experiments the maximum absolute error in the

31

determination of 1S0-labels was ±0.10%. Therefore a statement such as"retention of label was observed” should read "relative loss of labelwas 5% or less".

16Thus the mechanism resposible for the loss of 0 when a labeledaldehyde is treated with acetic anhydride (fig. 2-13) does not applyhere: OAc

Figure 2-13(Ac)20 + R -C H 2—C R — CHj— C R — CH = CH — OAc + HOAc

'OAc

cf. Houben-Weyl, Methoden der Organischen Chemie, Georg Thieme Verlag,Stuttgart, Bd 7/1, 442 (1954).

27) When camphor is treated with trichloroacetic acid anhydride (110-20 )a geminal di-ester is formed, 2,2-dihydroxy-camphene-di-trichloro-acetate which decomposes to give after a Wagner-Meerwein rearrangement1-hydroxy-camphene-trichloroacetate as the primary product (J. Libman,M. Sprecher and Y. Mazur, Tetrahedron, 25, 1679 (1969)).

28) Thls quantity of water (0.3g) was chosen because it would have beenformed when selenium dioxide has been added to the reaction mixtureand had oxidized all of the Ketone and nothing else.

29) J.J. Postowsky and B.P. Lugowkin, Ber., 6J3, 854 (1935).L. Rappen, J. Pr.akt. Chem., n.F. 157, 196 (1941).

30) A sample of camphorquinone prepared from labeled camphor21* had a labelof 1.60% 1S0, and the fragment (M-C0) a label of 0.40% 0 (15eVspectrum). If both carbonyl groups were equivalent, or if we had arandomly labeled diketone, we should expect the fragment (M-CO) to have

A ga label of 0.80% 0.

31) Assuming that thB "chain branching rule” (Cf. F.W. McLafferty.Interpretation of Mass Spectra, W.A. Benjamin Inc., 82 (1967)) can beused to predict that in camphorquinone the bond between C1 and C2 isbroken preferential to the bond between C3 and C4 , we conclude fromthe labels of 31) that 2-”*SQ-camphorquinone is the main or possibly theonly reaction product. If preference for bond rupture should beopposite to the "chain branching rule", then 3-180-camphorquinone isthe main or the only reaction product, and interchange of oxygen atomswithin a molecule has taken place.

32) J. Vène, Compt. Rend., 216, 272 (1943).33) Labeled selenium dioxide is commercially available (Miles Laboratories

Inc.)

32

3<t) The absolute configurations follow from the absolute configuration ofcamphor (M.G. Northolt and J.H. Palm, Rec. Trav. Chim., 85, 143 (1966))and the relative configurations of fenchone (1) and camphor (A. Fredgaand J.K. Misttinen, Acta Chem. Scand., 1, 317 (1947)],

3S) For syntheses of a-fenchene (4) the reader is referred to:a/ J.L. Simonsen, The Terpenes, Cambridge University Press, 2nd ed.,

vol'. 2, 538 (1949).b/ E. Gildemeister and Fr. Hoffmann, Die Aetherischen Oele, Akademie-

Verlag, Berlin, 4. Aufl.. Bd Ilia, 197 (1960).c/ V. Mattinen, Ann. Acad. Sc. Fennicae, All 106, 20 (1961).

) All syntheses of a-fenchene35 involve a Wagner-Meerwein rearrangementof the fenchyl-cation (15). From 15 the cations of a- and B-fenchene,— reap* i7* may be formed (fig. 2-14). Formation of 8-fenchenB (9) isvery undesirable because it can only be separated from a-fenchene bydistillation with great difficulty. Whether B-fenchene will be formeddepends on the reaction conditions. As is depicted in fig. 2-8 we haveprepared a-fenchene from fenchylamine, and did not expect the formationof B-fenchene, because under the same conditions from the borny1-cationMS) optically pure camphene (20a) 37) is formed. Thus under thoseconditions the camphene cations M9a,b) do not equilibrate, becausethat would bring about racemisation.

Figure 2-14 Wagner-Meerwein rearrangements (simplified).

ch2 ch2-

37) W.Hückel and,W. Tappe, Ber., 2/’69 (1936).W. Hückel, Ann., 549, 186 (1941).But a higher angle of rotation has been recorded for camphene, of.J.P. Bain, A.H. Best, B.L. Hampton, G.A. Hawkins and L.J. Kitchen,

J. Amer. Chem. Soc., 72, 3124 (1950).38) Unfortunately the CD of B-fenchocamphoronequinone (11) has not been

published, but if we assume that its strongest CD band in the region

33

250-520nm has Ae=0.1, which is a rather low value, then we would havedetected 11 by CD if its concentration in a-fenchocamphoronequinone

had been >0,35% .39) The presence of doubly labeled dikBtone (0,084] is due to the natural

A Q

abundance of 0 in the oxidizing agent.**0) jn this contxt it may be of interest to mention some data found in the

literature.

Figure 2-15 o 312 13 U

The yellow compound dehydronorcamphorquinone (1£) gives a colourlesssolution in water. A hydrate is postulated1*1. Thus this diketone mightundergo uncatalyzed oxygen exchange with water, whereas oxygen exchangebetween water and a ketone requires catalysis1*2./ Rassat1*3 states thatisofenchonequinone M3] is hydrated easily./ Some norsteroids with ano-diketone chromophore in the unsaturated A-ring (14) can be isolatedas mono-hydrates1*1*./ Cyclobutane-1,2-dione even reacts with water togive a-hydroxy-cyclopropanecarboxylic acid1*5.

41) h .-D. Scharf, W. Droste and R. Liebig, Angew. Chem., jlB, 195 (1968).42) This statement does not hold at elevated temperatures, for example

cyclopentanone recovered after heating in a sealed tube (2 hours, 150 )cyclopentanone (1ml), THF (1ml) and labeled water (0.5g, 12.062 at.%1 8 0 -21)) had a label of 7.33% 180. For a similar though lessconvincing experiment see M. Cohn and H.C. (Jrey, J. Amer. Chem. Soc.,

60, 679 (1938).

43) n,-p. Gervais and A. Rassat, Bull. Soc. Chim. Fr., 744 (1961).44) j. Kubota and F. Hayashi, Tetrahedron, 23, 999 (1967).**5) J.-ft. Conia and J.M. Denis, Tetrahedron Letters, (1971) (30) 2845.**6) W. Hückel and M. Sachs, Ann., 498, 166 (1932)**7) C. Coulombeau and A. Rassat, Bull. So.c. Chim. Fr., 3752 (1966).48) The angles of rotation of a-fenchocamphorone in MeQH and EtOH are

identical within the experimental error.**9) E.J. Corey and J.P. Schaefer, J. Amer. Chem. Soc., 82, 918 (1960).

J.P. Schaefer, J. Amer. Chem. Soc., 84, 713, 717 (1962).50j it is possible to prove rigorously, that oxidation of 7. is n°t

accompanied by racemisation. In order to prove this has to^beprepared, .enriched in 13C in the 2- or 3-position. This C- 0-7 has

34

t o be o x id iz e d to g iv e J3. Use has t o be made o f f ra g m e n ta t io n re a c t io n s

in th e mass s p e c tro g ra p h : m o le c u la r io n s o f norcam phorqu inones lo s e CO

and OCCO v e ry ea sy . We can e x c lu d e ra c e m is a t io n i f : 1 / th e fragm e n t13

(M- 56 ) i s n o t e n r ic h e d in C, 2 / i t fo l lo w s fro m measurement o f (M]

th a t 8 i s la b e le d s p e c i f i c a l l y , 3 / i t i s p ro ved by measurement o f13 18(M-CO) th a t o x id a t io n o f 2 - C -2 - 0 -7 e .g . g iv e s r is e e x c lu s iv e ly to

2 - C -2 - 0 -8 . T h is i s p o s s ib le because s c ra m b lin g o f °0 ( “ in v e r s io n1 3o f th e a b s o lu te c o n f ig u r a t io n i f th e m ol. was n o t e n r ic h e d in c)

13 18means fo rm a t io n o f 2 - C -3 - 0 - ^ w h ich has a s t r u c tu r e o f th e m u l t ip le t

(M-CO) d i f f e r e n t fro m 2 - ^ 3C -2 -" '80 -8 , c f . f i g . 2 -1 6 .

F ig u re 2-16 A f ra g m e n ta t io n re a c t io n o f 8 la b e le d w ith 13C and 180in th e chrom ophore (R =C^H ,_).

r i3„ is -| (+) - _ (♦) - -

— u

_R<?c=v- 2 C O 13 18

R — C = 0 4 12 16R — C = 0

m /e =129 m/e = l2 6

13 182 - C -2 - 0 - j) g iv e s in th e fragm e n t (M-CO) a r e la t iv e in c re a s e o fin t e n s i t y o f th e peak f o r m/e«129 as compared w ith u n la b e le d 8.

r 13 16 (♦> |« )

2^ - c = o

* * 0 2 ! 18L v c = o .

- 2 C 0 , 13 16R ------ C = 0

« 12 18R — C = 0

m / e =12 7 m/ e =128

13 182 - C -3 - 0t£ g iv e s in th e fra g m e n t (M-CO) a r e la t iv e in c re a s e o fin t e n s i t y o f th e peaks f o r m /e=127,128 as compared w ith u n la b e le d 8.

51) W.C.M.C. Kokke and L .J . O o s te rh o f f , J . Amer. Chem. S o c . , 94 , 7583

(1 9 7 2 ).

52) The f a c t o r used t o c o r r e c t th e observed CD f o r o p t ic a l and is o to p ic a l

im p u r it y was 1 0 0 0 0 /(4 8 .0 5 *9 0 .7 ) . 9 0 .7 s tan ds f o r th e o p t ic a l p u r i t y o f16 1 8 '

th e 0 - O -d ik e to n e , and 48 .05 f o r i t s is o to p ic a l p u r i t y , i . e . th e18pe rce n ta g e o f m o ls . la b e le d w ith one 0.

53 ) C. Sna tzke and H.-W . F e h lh a b e r, A n n ., 66 3 . 123 (1 9 6 2 ).

5I*) F. D a lla c k e r , L. A lro g g e n , H. K r in g s , B. La u r and M. L ip p , A n n ., 64 7 ,

34 (1 9 6 1 ).

55) O x id a t io n o f o -m e th y le n e camphor w ith h ig h ly la b e le d RuO i s n o t

p o s s ib le because th e l a t t e r compound is n o t c o m m e rc ia lly a v a i la b le

(a c c o rd in g t o o u r co rrespondence w ith M ile s L a b o ra to r ie s I n c . ) .

3®) An u n p u b lis h e d o z o n is a t io n p ro ced u re was used, w h ich was deve loped a t

S h e ll Research in Amsterdam.

) Sodium a c e ta te is known to re a c t in th e same manner w ith a -b rom o-

35

camphor t o g iv e a p ro d u c t C ,QH ^ O , c f . 59) .

58) We fou nd in th e l i t e r a t u r e a n o th e r example o f th e a b s t ra c t io n o f

hydrogen brom ide by s i l v e r a c e ta te : 1 ,2 -d ib ro m o -c y c lo h e x a n e g iv e s w ith

s iv e r a c e ta te 1 -b ro m o -c y c lo h e x -2 -e n e . C f. R. C o rn u b e rt, A. R io and

P. S é n é ch a l, B u l l . Soc. Chim. F r . , 46 (1 9 5 6 ).

59 ) W.Z. A n tk o w ia k , B u l l . Acad. P o l. S c i . , S e r. S c i. C h im ., 14, 517 [1 9 6 6 ).

88 ) R. F e r r ie r , Compt. R end ., 22 0 , 461 (1 9 4 6 ).

G. C lém en t, M. V i lk a s , G. Dupont and R. D u lo u , Compt. R end ., 242,

1184 (1 9 5 6 ).

T h is i n s t a b i l i t y o f 2 -hydroxy-3 -b rom o-cam phane i s due t o th e easy

a u to x y d a tio n o f t h i s compound59 t o g iv e camphor and cam phorquinone.

6 1 ) M .L . More , O rg a n ic R e a c tio n s , v o l . 5 , 301.

62 ) H. Rupe, F r . B u x to r f and W. F l a t t , H e lv . Chim. A c ta , 22.» 1°26 (1 9 3 0 ).

63 ) F o r some more exam ples o f t h i s anomalous cou rse o f th e L e u c k a rt

re a c t io n see

H . T . C la rk e , H .B . G i l le s p ie and S .Z . W eisshaus, J . Amer. Chem. S o c .,

SS_, 4571 (1 9 3 3 ).

W.E. Parkham , W.T. H u n te r , R. Hanson and T . L a h r, J . Amer. Chem. S o c .,

74 , 5646 (1 9 5 2 ).

6**) F o r re fe re n c e s see : Houben-W eyl, Methoden d e r O rgan ischen Chemie,

Georg Thieme V e r la g , S t u t t g a r t , Bd 6 /3 , 272 (1 9 6 5 ).

65) A. M c K il lo p , J .D . H u n t, R.D. N a y lo r and E .C . T a y lo r , J . Amer. Chem.

S o c . , 93 , 4918 (1 9 7 1 ).

6 6 ) J .H . Beynon and A .E . W il l ia m s , Mass and Abundance T ab les f o r Use in

Mass S p e c tro s c o p y , E ls e v ie r P u b lis h in g C oup ., (1 9 6 3 ).

67 ) W. Reusch, M.W. D iC a r lo and L . T ra y n o r , J . O rg. Chem., 2 £ , 1711 (1 9 6 1 ).

58) F .H . Lees, J . Chem. S o c ., j33^ 152 (1 9 0 3 ).

59 ) 0. W a lla c h , A n n ., 2 6 3 , 136 (1 8 9 1 ).

70) 0 . W a lla c h , A n n ., 2 7 2 , 105 (1 8 9 3 ).

73) W. H O cke l, B e r. , J)0_, 39 (1 9 4 7 ).

72) G. Komppa and S .V . H in t ik k a , B e r . , 47» 936 (1 9 1 4 ).

R .H. R o s c h ie r , Ann. Acad. Sc. F e n n ica e , A10 ( 1 ) , 56 (1 9 1 7 ).

73 ) A .F . Thomas and B. W il lh a lm , T e tra h e d ro n L e t te r s , (1965) (18 ) 1309.

J .M . J e rk u n ic a , S. B o rc ic and D .E. Sunko, T e tra h e d ro n L e t te r s ,

(1965) (49 ) 4465.

A .F . Thomas, R .A. S c h n e id e r and J . M e inw a ld , J . Amer. Chem. S o c .,

89 , 68 (1 9 6 7 ).

36

T .T . Thomas, J . Amer. Chem. S o c ., 9 2 , 1446 (1 9 7 0 ).

7“ ) See 5**).

75) G. Sna tzke and J . H im m e lre ic h , T e tra h e d ro n , 2 3 , 4354 (1 9 6 7 ).

76 ) H. K r ie g e r , Suomen K e m is t i le h t i , 3S, 10 (1 9 6 2 ).

77) K. A ld e r and A. G r e l l , B e r . , 8£ , 2198 (1 9 5 6 ).

78) S.M. M alm gren, B e r . , 3£ , 3910 (1 9 0 2 ); 36 , 2608 (1 9 0 3 ).

79) J . B re d t and W.H. P e rk in , J . Chem. S o c ., 103 , 2210 (1 9 1 3 ); f o r th e

p u r i f i c a t i o n com pare: L. C la is e n and 0 . Manasse, A n n ., 27 4 , 73 (1 8 9 3 ).

80) P. Duden and W. P r itz k o w , B e r . , 32_, 1539 (1 8 9 9 ).

81 ) D u rin g th e s e p a ra tio n o f t h i s m ix tu re th e s p l i t t e r o f th e p re p .

gaschrom atograph go t c lo g g e d , p ro b a b ly due t o d e co m p o s itio n o f th e

unknown compound.

% % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % %

37

CHAPTER THREE

1 -DEUTERO-ct-FENCHOCAMPHORONEQUINONE

OPTICAL ACTIVITY DUE TO ISOTOPIC SUBSTITUTION. CIRCULAR DICHROISM

OF (1 R )-[1 D ] -a-FENCHOCAMPHORONEQUINONE.

S i r :

In re c e n t y e a rs s tu d y o f th e m o le c u la r geom etry o f s m a ll c y c l i c

m o le cu le s has y ie ld e d th e in fo rm a t io n th a t such m o le cu le s a re n o t

n e c e s s a r i ly r i g i d , b u t in some cases may be deform ed e a s i ly , w h ich r e s u l t s

in low ly in g no rm a l m odes*, o r even may e x is t in c o n fo rm a tio n s as haë been

shown in th e case o f f o u r membered r in g s 2 and th e b ic y c lo [ 2 . 2 . 2J oc tane

s k e le to n 3 . In th e b ic y c lo [2 .2 .1 ] heptane s e r ie s o ccu rre n ce o f c o n fo rm a tio n a l

e q u i l i b r i a has n o t y e t been e s ta b lis h e d a lth o u g h v a le n ce fo rc e c a lc u la t io n s

**) in d ic a te d t h a t such e q u i l i b r i a may e x i s t .

in cyclohexane

(1R)-[ 1D]- a - fenchocamphoronequinone

Because o f o u r in te r e s t in th e sp e c tro s c o p y o f a -d ik e to n e s in th e

b ic y c lo [ 2 .2 . l ] heptane s e r ie s , w h ich le d us t o s tu d y th e o p t ic a l a c t i v i t y

due t o 10O - s u b s t i tu t io n in a -fenchocam phoronequ inone5 ( I ) (see c h a p te r 2 ) ,

we wondered i f is o to p ic a l o p t ic a l a c t i v i t y c o u ld be used as a t o o l f o r th e

d e te c t io n o f c o n fo rm a t io n a l e q u i l i b r i a : i f I sho u ld e x is t in co n fo rm e rs ,

each w ith a tw is te d chrom ophore as in cam phorquinone5 , th e n s p e c i f ic

36

in cyclohexane

(1R)-|1D)-a fenchocamphoronequinone

F ig u re 3 -2 7 )

F ig u re 3 -3 The s y n th e s is o f th et i t l e compound fro m( +) - (1 R) - camphor.

D

COOH

rep la cem en t o f a hydrogen atom by d e u te r iu m m ig h t s h i f t th e e q u i l ib r iu m

between th e con fo rm ers and d e te c t io n o f CD w ou ld be p o s s ib le , p ro v id e d th ee f f e c t were la rg e enough.

We s y n th e s iz e d (1 R ) - [ id ] - a-fenchocam phoronequ inone ( I I ) and r e p o r t t h a t

measurement o f th e CD o f I I was p o s s ib le ( f i g . 3-1 8 9 ) ) . I t i s th e f i r s t

example o f a CD cu rve o f a compound whose o p t ic a l a c t i v i t y i s due o n ly t o

d e u te riu m s u b s t i t u t io n 18. F ig . 3 -2 shows th e c a lc u la te d c o n t r ib u t io n 11 to

th e ORD o f th e CD band o f I I in th e v is ib le re g io n . The ro u te fo l lo w e d in

th e s y n th e s is o f I I i s shown in f i g . 3 -3 .

However, as th e observed CD o f I I i s a lm os t in de pen de n t o f s o lv e n t and

te m p e ra tu re 12 we cannot a s c r ib e th e observed CD t o a c o n fo rm a tio n a l

e q u i l ib r iu m : e i t h e r I does n o t e x is t in con fo rm ers o r in t r o d u c t io n o f

d e u te riu m is in s u f f i c i e n t t o s h i f t such an e q u i l ib r iu m .

F o r th e e x p la n a t io n o f th e CD cu rve ( f i g . 3 - 1 ) , w h ich has a d i r e c t

b e a r in g on th e th e o ry o f th e e le c t r o n ic and g e o m e tr ic a l s t r u c tu r e o f

39

a -d ic a rb o n y l compounds, s e v e ra l p o s s ib i l i t i e s may be th o u g h t o f ; One may

c o n s id e r m ix in g o f sym m etric and a n t is y m m e tr ic v ib r a t io n a l modes due t o

asym m etric d i s t r i b u t i o n o f mass. One may a ls o c o n s id e r th e in f lu e n c e o f

is o to p e s on th e geom etry o f th e m o le cu le v ia a n h a rm o n ic ity o f p o t e n t ia l

c u rv e s . F o r exam ple , th e geom etry o f I changes s l i g h t l y on d e u te riü m

s u b s t i t u t io n , because as a consequence o f a n h a rm o n ic ity th e C-H and C-D

e q u i l ib r iu m bond le n g th s d i f f e r by abou t 0 .0 0 4 ° 13 l l M .

R e fe re n c e s .1) Some exam ples o f s m a ll c y c l i c compounds w ith low ly in g no rm a l modes

are fo u r membered r in g s j b ic y c lo | 2 . 1 . 1 1 he xa n e -2 -o n e , 140±15cm ,

(D. C o ffe y , J r . and T .E . H ooker, J . M o l. S p e c try , 40 , 158 (1971 ) ) j

th io c a m p h o r, 96cm '1 * 3 * 5 6 * 8 C C C ^r, o n ly a c t iv e in Ramans cam phor, 116cm

( n u jo l) s no rcam phor, 128cm '1 ( n u jo l ) ; cam phorquinone. 163cm ( n u jo l ) .

(The f a r - I R s p e c tra o f th e s e n o rbo m ane d e r iv a t iv e s have been

measured by M r. G .F . P o th o f f , F ree U n iv e r s i t y , Amsterdam, w ith a

G rubb-P arsons in te r fe r o m e te r ) .

2) F o r e v id e n ce fro m m icrowave s p e c tro s c o p y sees

L .H . Scharpen and V.W. L a u r ie , J . Chem. P h y s .. 49., 221 , 3041 (1 9 6 8 ).

A .C . L u n tz , J . Chem. P h y s ., 5£ , 1109 (1 9 6 9 ).

A c o n fo rm a t io n a l e q u i l ib r iu m s h o u ld be th e reason o f a la rg e s o lv e n t

e f f e c t on th e CD o f 2 , 2 , 3- t r im e th y lc y c lo b u ta n o n e , c f . J . G ore,

C. D je ra s s i and J .-M . C o n ia , B u l l . S oc . Chim. F r . , (1967) 950.

3) 0 . E lm e r and J .D . D u n itz , H e lv . Chim. A c ta , 52_ . 1861 (1 9 6 9 ).

E. H i r o ta , J . M o l. S p e c try . 38 , 367 (1971)

“*) C. A lto n a and M. S u n d ra lin g a n , J . Amer. Chem. S o c ., 92 , 1995 (1 9 7 0 ).

5 ) W.C.M.C. Kokke and L .J . O o s te rh o f f , J . Amer. Chem. S o c ., £ 4 , 7583(1 9 7 2 ).

6 ) W. Hug and G. W agn iè re , H e lv . Chim. A c ta , £ 4 , 633 (1 9 7 1 ).

E. Charney and L . T s a i. J . Amer. Chem. S o c ., 93.* 7123 (1 9 7 1 ).

In bo th p u b l ic a t io n s i t i s p o s tu la te d t h a t th e s k e le to n o f camphor­

qu inone sh o u ld be tw is te d , b u t th e re i s d isag reem e n t as t o th e sense

o f t w i s t . X -ra y a n a ly s is p ro ved th e p o s tu la te o f Charney & T s a i ( lo c .

c i t . ) t o be c o r r e c t , a t le a s t in th e s o l id s ta te (L . T s a i, E. C harney.

J .V . S i lv e r t o n and W.M. B r ig h t , t o be p u b l is h e d ) .

7) The c a lc u la te d a m p litu d e o f t h i s cu rve i s 9 7 .5 .

8 ) T h is CD has been c o r re c te d t o o p t ic a l and is o to p ic a l p u r i t y .

40

) The small band in the CD of II at 345.Onm is also present in the CD ofcamphorquinone, but it was not depicted in fig. 2-2 because of its low

-3intensity (346.5nm, Ae=+29.6*10 (cyclohexane)).1®) For reviews on hydrogen-deuterium asymmetry see:

D. Arigoni and E.L. Eliel, Top. Stereochem., vol. 4, 122.L. Verbit, Prog. Phys. Org. Chem., vol. 7, 51.

11) C.A. Emeis, L.J. Oosterhoff and Gonda de Vries. Proc. Roy. Soc.,A297, 54 (1967).

12) The CD was measured in cyclohexane, acetonitrile and 2-methyl-THF atroom temperature, and in the latter solvent also at -110°.

13) Such small differences in bond lengths follow from microwavB spectros-copical studies. Cf. J.E. Wollrab, Rotational Spectra and MolecularStructure, Academic Press (1967), p 110.

ll+) To obtain more information on the influence of small variations inbond lengths on optical activity, we suggest the synthesis of opticallyactive L’l -7,7-dimethyl-bicyclo[2.1 . l]hexane-2-one and other simpleKetones with optical activity due to the substitution of D a withrespect to the carbonyl group.

W.C.M.C. KokkeL.J. OosterhoffDepartment of Theoretical Organic Chemistry,University of Leiden, P.0. Box 75,Leiden, The Netherlands.

% % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % %

41

THE SYNTHESIS OF MR)-[1D]-a-FENCHOCAMPHORONEQUINONE.

W.C.M.C. Kokke and F .A . V a rk e v is s e r ,

D epartm ent o f T h e o re t ic a l O rg a n ic C h e m is try , U n iv e r s i ty o f L e id e n ,

P .Ü . Box 75, L e id e n , The N e th e r la n d s .

Summary.

The t i t l e compound (6 ) was p re p a re d fro m M R )-[1D J-a -fench oca m ph o ron e ( 5 ) ,

w h ich was o b ta in e d fro m (+ )-ca m ph o r (1_) v ia k e to p in ic a c id (2 ^ .

In t r o d u c t io n o f d e u te riu m was a ch ie ved by LAD re d u c t io n o f 1 -b rom o-a -

-fenchocam phorone (3 K a d e g ra d a tio n p ro d u c t o f k e to p in ic a c id (2 ^ .

( 1 R ) - [ id ] - ct-Fenchocam phoronequinone, a d ik e to n e whose o p t ic a l a c t i v i t y i s

due o n ly to d e u te r iu m s u b s t i t u t io n , showed a s m a ll b u t m easurab le e f f e c t

in CD o f b o th low in t e n s i t y a b s o rp tio n bands in th e re g io n 250-500nm.

I n t r o d u c t io n .

In th e re c e n t l i t e r a t u r e s e v e ra l a u th o rs have p u b lis h e d r e s u l t s 16 o f

c a lc u la t io n s on th e o p t ic a l a c t i v i t y o f th e tw is te d a -d ic a rb o n y l

chrom ophore . G ly o x a l was used as a model compound f o r thesB c a lc u la t io n s .

I t was fo u n d th a t when in c is - g ly o x a l th e fo rm y l groups a re s l i g h t l y

ro ta te d w i th re s p e c t to each o th e r around th e C-C bond, th e C o tto n e f f e c t s

a s s o c ia te d w ith th e two low in t e n s i t y a b s o rp tio n bands a t lo n g e s t wave­

le n g th s h o u ld have an o p p o s ite s ig n . As i t i s known th a t th e C o tto n e f f e c t s

in cam phorquinone a t abou t 300 and 4B0nm have an o p p o s ite s ig n (see f i g .

2 - 2 ) , th e se a u th o rs 16 f e l t t h a t th e CD o f cam phorquinone c o r ro b o ra te d t h e i r

p r e d ic t io n s and th e y assumed t w is t to be p re s e n t in i t s a -d ic a rb o n y l

chrom ophore .18

In v ie w o f th e s u c c e s fu l s y n th e s is o f M R )-2 - O -a-fenchocam phorone-

qu inone and o f th e measurement o f i t s CD (see c h a p te r 2 ) i t seemed w o rth

w h ile to s y n th e s iz e a s im i la r compound w ith o p t ic a l a c t i v i t y due to

d e u te riu m s u b s t i t u t io n in o rd e r to c o n t r ib u te to th e knowledge o f th e

e le c t r o n ic and g e o m e tr ic a l s t r u c tu r e o f th e a - d ic a rb o n y l group in

no rcam p horq u inon es .

We were s u c c e s s fu l in s y n th e s iz in g M R )-[1 D ]-a -fe n ch o ca m p h o ro n e q u in o n e

(6 ) w h ich showed a CD spec trum ( f i g . 3-1 17) ) d i f f e r i n g in many re s p e c tsA R

fro m th e CD spec trum o f (1 R )-2 - D -a -fenchocam phoronequ inone ( f i g . 2 -1 ) .

T h is r e s u l t sug ge s ts th a t in g e n e ra l o p t ic a l a c t i v i t y due to is o to p ic

s u b s t i t u t io n may p ro v id e new in fo rm a t io n abou t th e s t r u c tu r e o f

42

chromophores.

Details of thB synthesis.

COOH

<&m-é r - $r -8 9 10 11 12

Figure 3-4 The absolute configurationsof the compounds aredepicted in the figures21.

COOH

Figure 3-5 6 5 4

The route we followed to (1R)-[1dJ-a-fenchocamphoronequinone (6)Cfig. 3-5) is obvious once one Knows that the bridge-head methyl group incamphor (1_) can be converted into a methyl group in three steps.

To investigate the experimental conditions necessary for the replace­ment of the bridge-head halogen in 3_ or 9_ we chose oi-bromo-camphor as amodel compound. It was found that the halogen was resistent to LAH inboiling THF: the carbonyl group could be reduced selectively. However,when the reduction was carried out in N-methylmorpholine22, a solventpermitting a higher reaction temperature, the halogen was reduced as well.

The bridge-head halogen compounds j) and 9_ were less reactive thanct-bromo-camphor in LAH reduction in N-methylmorpholine, and a large excessof LAH and a reaction time of several days were necessary to achievecomplete reduction.

After it was verified that o-fenchocamphorone (11) did not containannoying impurities { it could be oxidized to give a-fenchocamphorone-quinone (12) which was inactive in CD } the desired deuterium containingdiketone (6) was synthesized following the same route.

43

E x p e r im e n ta l.

M e lt in g p o in ts a re n o t c o r re c te d ! an g les o f r o t a t io n were measured w ith a

P e rk in -E lm e r p o la r im e te r [m odel 131) a t room te m p e ra tu re . Labe ls were

c a lc u la te d fro m peak in t e n s i t i e s o f mass s p e c tra o b ta in e d w ith a MS-9 mass

s p e c tro m e te r . NMR s h i f t s a re w ith re s p e c t t o TMS.

K e to p ln ic a c id (2 ) can be p re p a re d in th re e s te p s fro m camphor23 v ia

c a m p h o r-1 0 -s u lp h o n ic a c id and c a m p h o r-1 0 -s u lp h o n y l c h lo r id e . Some la b o r can

be saved i f one s t a r t s w ith ( + ) - (1 S )-c a m p h o r-1 0 -s u lp h o n ic a c id w h ich is

c o m m e rc ia lly a v a i la b le .

O x id a t io n 21* o f (1S) -c a m p h o r-1 0 -s u lp h o n y l c h lo r id e and r e c r y s t a l l i s a t i o n o f

th e c rude p ro d u c t fro m w a te r gave (1S)-2_ in 20 .9 -24 .5% y ie ld , mp 226-.8 ,

[ a ] D+ 2 5 .0 ° (MeOH). T h is low y ie ld i s in d isag reem en t w i th th e y ie ld c la im e d

in th e p ro ce d u re fo llo w e d 21* (38 -43% ). We o b ta in e d a b y -p ro d u c t in t h is

r e a c t io n : a w h ite compound su b lim e d on th e f l a t f la n g e l i d o f th e re a c t io n

v e s s e l. I t was id e n t i f i e d as (1 S )-1 0 -c h lo ro -c a m p h o r. Y ie ld 2 .7 -2 .9 % a f t e r

r e s u b l im a t io n , mp 1 3 0 -1 ° , [a 3 ^+ 3 9 .7 5 ° (C H C l^). NMR d a ta (C D C l^ ): tw o m e th y l

groups a t 6= 0 .9 67 , 1 .111ppm: hydrogens a tta c h e d t o C1Q: q u a r te t a t

6=3.69ppm , 2 2 .4 H z , J 2=12.2H z. T h is c h lo ro -c a m p h o r m ig h t have been form ed

d u r in g th e p re p a ra t io n o f th e s u lp h o n y l c h lo r id e because crude s u lp h o n y l

c h lo r id e was used f o r th e p re p a ra t io n o f 2 .

R e du c tion o f 2 2 5 ) w ith R a n e y -n ic k e l W-6 2 6 ) gave (1 S J -7 ,7 -d im e th y l-

n o rb o rn a n e -2 -o l-1 -c a rb o x y lic a c id 17] (m a in ly exo25 ) in 96% y ie ld .

(1S) - 7 ,7 - D im B th y l-n o rb o m a n e -2 -o l-1 - c a rb o x y lic a c id -a c e ta te (J3) was

p re p a re d fro m 7_ w i th a c e ty l c h lo r id e and p y r id in e , fo l lo w in g a p ro ce d u re 27

f o r th e e s t e r i f i c a t io n o f an iso m e r o f 3 .

H u n s d ie c k e r d e g ra d a tio n o f 8. The s i l v e r s a l t o f w h ich was s o lu b le in

e th e r and m e th a n o l, was t r e a te d w ith brom ine in carbon t e t r a c h lo r id e

a c c o rd in g t o "p ro c e d u re C" o f W ild e r and W ins ton2 ® who degrada ted

b ic y c lo | 2 . 2 .2 |o c ta n e - 1 - c a r b o x y l ic a c id . Y ie ld 69.5%: a m ix tu re o f

1 - c h lo r o - £ (29%) and 1-bromo-9^ (71%).

D e g ra d a tio n o f 2 w ith brom ine and m e rc u r ic o x id e in d ic h lo ro m e th a n e has

been re p o r te d 2®. We fo llo w e d t h is p ro c e d u re 2®. Because d e c a rb o x y la t io n

re a c t io n s as t h i s one are r a d ic a l r e a c t io n s , u s u a l ly th e d e s ire d p ro d u c t i s

n o t th e o n ly p ro d u c t , e .g . i t i s known th a t when a H u nsd ie cke r re a c t io n is

c a r r ie d o u t in carbon t e t r a c h lo r id e a ls o c h lo r in a te d p ro d u c t i s t o be

e x p e c te d 30 , as we observed a f t e r th e d e g ra d a tio n o f J3. A n a ly s is o f th e

r e a c t io n m ix tu re a f t e r th e d e g ra d a tio n o f 2_ showed th a t a b y -p ro d u c t was

44

form ed (20%) w h ich was id e n t i f i e d as a-fenchocam phorone (1 1 ) . F o rm a tio n o f

11 was n o t re p o r te d in 2 9 ) . No c h lo r in e c o n ta in in g p ro d u c t c o u ld be

d e te c te d .

The s o lv e n t was removed and th e crude p ro d u c t was d is s o lv e d in an e q u a l

volume o f MeOH; 1 -b rom o-a-fenchocam phorone (3_) was th e n removed by

f i l t r a t i o n a t -1 5 ° . Y ie ld 50-1%. T h is p ro d u c t, once r e c r y s t a l l is e d , was

used f o r f u r t h e r r e a c t io n s . P a r t o f i t was f u r t h e r p u r i f ie d by

r e c r y s t a l l i s a t i o n from h e p tan e . Then i t showed [a ] +73 .5 (MeOH), mp

1 9 0 -1 ° . NMR d a ta (C D C lg ): tw o m e th y l g roups a t 6= 0 .9 54 , 1.087ppm.

The sem lcarbazone o f 3 . f in e ne e d le s fro m a lc o h o l, canno t be used f o r th e

c h a r a c te r is a t io n o f 3 because o f i t s low s o l u b i l i t y w h ich does n o t p e rm it

measurement o f th e an g le o f r o t a t io n . I t has no sharp mp: d e co m p o s itio n

s t a r t s a t 2 3 0 ° j th e compound i s a l i q u i d a t 245 .

1-B rom o-q -fenchocam phoronequ inone . 3_ was o x id iz e d w ith se le n iu m d io x id e in

a c e t ic a n h y d r id e 31 to g iv e 1-b ro m o-a -fe ncho cam p horo ne qu ino ne , [a ]^ -3 6 6 °

(C H C lg ), mp 2 0 1 .5 -2 .0 ° , in 31.2% y ie ld a f t e r r e c r y s t a l l i s a t i o n (6x) from

h e p tan e . NNR d a ta o f t h i s d ik e to n e (C D C lg ): tw o m e th y l peaks a t 6= 1 .028 ,

1 . 187ppm.

LAH re d u c t io n s o f brom o-kB tones and h a lo - e s te r s . G e n e ra l: u n le s s s ta te d

o th e rw is e a s o lu t io n o f th e compound t o be reduced was added w ith o u t

s t i r r i n g t o a b o i l i n g m ix tu re o f LAH and s o lv e n t hea ted on an o i l b a th . The

p ro d u c t was a lw ays is o la te d by steam d i s t i l l a t i o n a f t e r w a te r had been

added t o d e s tro y th e excess o f u n re a c te d LAH, and s u f f i c ie n t h y d ro c h lo r ic

a c id t o a c id i f y th e m ix tu re . When th e condenser g o t c logged d u r in g th e

steam d i s t i l l a t i o n i t was c le a n e d w ith d ic h lo ro m e th a n e .

R e du ction o f q -b rom o-cam phor.

- A m ix tu re o f a -b rom o-cam phor (2 0 g ) , LAH (5g =204% excess) and THF (100m l)

was re f lu x e d o v e r n ig h t . A n a ly s is o f th e p ro d u c t showed th a t o n ly th e

c a rb o n y l group had been red uce d : no b o rn e o l o r is o b o rn e o l were fo rm ed . Thus

a s o lv e n t was re q u ire d p e r m it t in g a h ig h e r re a c t io n te m p e ra tu re .

- A m ix tu re o f a -brom o-cam phor (20g) , LAH (5 g =204% excess) and N -m e th y l-

m o rp h o lin e (100m l) was r e f lu x e d o v e rn ig h t . Then re d u c t io n was c o m p le te .

R e d u c tio n o f 9 .

- When 9 (20g) was r e f lu x e d o v e rn ig h t w i th LAH (5g =118% excess) in

N -m e th y lm o rp h o lin e (1 0 0 m l) , i t was fou nd t h a t o n ly 15% o f th e p ro d u c t was

a-fenchocam phoro l. (10) , th e re m a in d e r was 1 -h a lo -a - fe n c h o c a m p h o ro l. C le a r ly

a lo n g e r re a c t io n t im e and a la r g e r excess o f LAH were n e ce ssa ry .

45

- A m ix tu re o f 9_ (20g) , LAH ( 1 3 .5g «488% exce ss ] and N -m e th y lm o rp h o lin e

(120m l) was re f lu x e d f o r one week. Then re d u c t io n was com p le te .

- A s o lu t io n o f 9 (3 3 .5g) in d ig ly m (50m l) was added to a m ix tu re o f d ig ly m

(120m l) and LAH (16g =318% e x c e s s ) , p la c e d in a b a th a t 150°. The m ix tu re

was hea ted o v e rn ig h t a t 150°. The p ro d u c t c o n s is te d o f 1^_ (75%) and

1-h a lo -o i- fe n c h o c a m p h o ro l (25%).

R e du c tion o f 3 and p re p a ra t io n o f q -fenchocam phoronequ inone ( 12) .

- A m ix tu re o f 3 (35 g) , LAH (19g =529% excess) and N-methy lm o rp h o lin e

(200m l) was r e f lu x e d f o r 6 days. Then re d u c t io n was c o m p le te . I t fo llo w e d

fro m G .L .C .-m easurem en ts (DEGA colum n) t h a t we had o b ta in e d a m ix tu re o f

exo-T>10 (87.1% ) and endo-10 (12 .9% ).

a / A f te r th e re d u c t io n p a r t o f th e s o lu t io n o f th e p ro d u c t in d ic h lo r o r

methane was e va p o ra te d and th e re s id u e s u b lim e d . T h is exo-endo m ix tu re

(1 .2 g =5.3%) had [ a ] Q-1 2 .1 3 0 (C H C lg ).

b / A n o th e r p a r t o f th e p ro d u c t, meant f o r th e p re p a ra t io n o f 12 , was

p u r i f ie d by p re p . G .L .C . (SE-30 colum n) under th e same c o n d it io n s as th e

d e u te riu m c o n ta in in g a lc o h o l 4 was p u r i f ie d (see b e lo w ) . The p u r i f ie d

a lc o h o l 1 ^ was th e n o x id iz e d w ith RuO in CH^Cl^ t o g iv e o - fe n c h o -

camphorone (11) (2 .8 g =12.6% based on 3 ) .

To show th a t 11 d id n o t c o n ta in an no y ing im p u r i t ie s , crude ^1_ (2 .0 g ) was

o x id iz e d ^ 1 w i th se le n iu m d io x id e in a c e t ic a n h y d r id e . To th e p ro d u c t

was added d ic h lo ro m e th a n e , i t was f i l t e r e d , washed f r e e from a c id and

d i s t i l l e d . The d i s t i l l a t e was p u r i f ie d by p re p . G .L .C . (SE-30 colum n) in

o rd e r t o remove u n re a c te d 11. Y ie ld o f 12 a f t e r s u b lim a t io n 1 .5 g (=68%),

mp 1 3 8 .5 -9 .5 ° . F o r tu n a te ly no CD o f 12_ c o u ld be d e te c te d , in d ic a t in g th e

absence o f annoy ing im p u r i t ie s . NMR d a ta o f 12 (CDC1_): two m e th y l peaks

a t 6= 1 .0 94 , 1.140ppm.

G .L .C .-m easurem ent o f c rude 11_ in d ic a te d th e presence o f tw o im p u r i t ie s .

F o r measurements 11 was p u r i f ie d by p re p . G .L .C . (Carbowax co lu m n ). The

most abundant im p u r it y (2.0% ) w ith a r e te n t io n t im e s h o r te r th a n 11

c o u ld c o m p le te ly be rem oved, whereas th e o th e r im p u r it y (0.2% ) w ith a

r e te n t io n t im e lo n g e r th a n 1_1_ c o u ld p a r t i a l l y be removed. P u r i f ie d

(1R )-11 had mp 1 0 0 -5 ° , [ a ] D+ 6 6 .5 ° (ab s . EtOH) j in NMR th e tw o m e th y l .

peaks c o in c id e d a t 6=1.043ppm . L i t . * ® : [a j ^+ 7 3 .9 4 ° (E tO H ), mp

1 1 3 .0 -3 .5 ° .

c / The re m a in d e r o f th e s o lu t io n o f c rude 1_0 in d ic h lo ro m e th a n e was coo le d

t o -1 5 ° . The c r y s ta ls [n e e d le s ] were removed by f i l t r a t i o n . Pure e x o -11

46

(6 .4 g *28.3% ) c o u ld be o b ta in e d by r e c r y s t a l l i s a t i o n o f th e s e need les

fro m p e n ta n e -d ic h lo ro m e th a n e 4 :1 (4 x ) : th e c r y s ta ls were removed by

f i l t r a t i o n a t -15 a f t e r e v e ry r e c r y s t a l l i s a t i o n .

Data o f pu re (1 R )-e x o -1 0 : mp 1 4 0 -1 ° . [a J p -1 5 .4 5 0 (CHC1 ) . NMR d a ta

(C O C lg): tw o m e th y l peaks a t 6 *0 .9 5 3 . 1.224ppm ; H a tta c h e d t o C :

q u a r te t , 6=3.842ppm, J ,|= 7 .3 H z , J2 =4 . 0Hz. From th e v a lu e s o f [a ] o f pure

e x o -1 £ and o f th e exo-endo m ix tu re i t f o l lo w s th a t (1R )-endo-10 has

[ o ] D+ 1 0 .3 ° (CHClg)

e v a p o ra t io n o f th e m o th e r - l iq u o rs o f th e r e c r y s t a l l i s a t i o n o f 10 gave

im pure 1£ (6 .9 5 g *3 0 .8 % ]. A d d it io n o f t h i s y ie ld and o f th e y ie ld s o f 10

and _11_ c la im e d unde r a / , b / and c / in d ic a te s t h a t th e y ie ld o b ta in e d in th e

re d u c t io n o f _3 was 77.0%.

C h a ra c te r is a t io n o f 11 . M a tt in e n 19 p u r i f ie d 1_1_ as th e sem ica rbazone . We

fou nd t h a t t h i s sem icarbazone c o u ld o n ly be r e c r y s t a l l is e d w ith

c o n s id e ra b le lo s s o f m a te r ia l fro m benzene o r w a te r -a lc o h o l 1 :1 . We

p re p a re d 32 th e 2 ,4 -d in it ro p h e n y lh y d ra z o n e o f 11 , mp 1 4 1 -2 ° , [a ] - 7 9 . 9 °

(CHCI3 ) , in about 50% y ie ld a f t e r r e c r y s t a l l i s a t i o n (4 x ) fro m a lc o h o l.

E xpe rim e n ts w i t h d e u te ra te d compounds. N o te : 3 necessa ry f o r th e

s y n th e s is o f bo th and 12 was o b ta in e d in th e same p re p a ra t io n .

A m ix tu re o f 3 (2 0 g ) , LAD (98% Dj a f r e s h 10g package (M e rc k ), 420%

e x c e s s ) , and N -m e th y lm o rp h o lin e (110m l) was r e f lu x e d f o r 6 days. Then

re d u c t io n was in c o m p le te 33 : 41.4% o f th e m ix tu re was d e u te ra te d a - fe n c h o -

cam phoro l (4^) j 58.6% was 1 -b ro m o -a -fe n c h o c a m p h o ro l. The tw o a lc o h o ls were

s e p a ra te d by p re p . G .L .C . (SE-30 c o lu m n ). Y ie ld o f b ro m o -a lc o h o l 8 .7 g

(=73.6% : y ie ld based on 3 and on th e c o m p o s it io n o f th e m ix tu re o f

re d u c t io n p ro d u c ts ) . NMR d a ta o f t h i s b ro m o -a lc o h o l (C D C 1J: tw o m e th y l

peaks a t 6= 0 .9 70 , 1.129ppm; as a consequence o f th e h ig h d e u te r iu m c o n te n t

o f ' t h e LAD used , H a tta c h e d t o C2 c o u ld n o t be d e te c te d by NMR.

— was o x id iz e d w ith RuO^ in CH^Cl^ t o g iv e (3 .4 g =64.6%: y ie ld based on

and on th e c o m p o s itio n o f th e m ix tu re o f re d u c t io n p ro d u c ts ) . O n ly 33.60%

o f 5_ was la b e le d w ith one d e u te r iu m and 1.77% was d o u b ly la b e le d w ith

d e u te r iu m .

5 (2 .0 g ) was o x id iz e d as in d ic a te d above, and gave a f t e r p u r i f i c a t i o n by

p re p . G .L .C . 6_ (1 .4 g *64 -s ), mp 1 3 7 .5 -9 .0 . 30.08% o f 6_ was la b e le d w ith one

D and 0.53% was d o u b ly la b e le d . T h is 6 was used f o r measurement o f CD3**.

The observed CD was n o t caused by im p u r i t ie s because :

1 / U n de u te ra te d d ik e to n e 1£, p re p a re d in th e same manner as 6 from 3 was

47

inactive in CD.2/ Recrystallisation of 6 (from heptane) did not affect the effect in CD.3/ j-p the observed effect in CD were due only to an impurity haying Ae-2

(i.e. a much larger effect in CD than camphorquinone), this impurityshould be present in the mixure for about 0.4%. Careful examination of5 with capillary columns (SE-30, DEGA) indicated that in ^ only the sameharmless impurities were present as in _11_ and in about the sameconcentration.

Although it cannot be proved that in every molecule of j3 the deuterium isattached to C., contamination of 6 with deuterated isomBrs is very unlikelysince there is no evidence for such isomerisations in the literature onLAD reductions.

Acknowledgement.The authors are indebted to Prof. L.J. Dosterhoff for his interest in thiswork, and to Prof. H. Wynberg for reading the manuscript. The CD measure­ments were carried out with an instrument built by Mr. Dekkers in thisdepartment.

References.16) W. Hug and G. Wanière, Helv. Chim. Acta. 54, 633 (1971).

E. Charney and L. Tsai, J. Amer. Chem. Soc., 93, 7123 (1971).In both publications it is assumed that the skeleton of camphorquinoneis twisted, but there is disagreement as to the sense of twist. FromX-ray analysis (L. Tsai. E. Charney, J.V. Silverton and W.M. Bright, tobe published) it has been concluded that the sense of twist advocatedby Charney and Tsai is correct, at least in the solid state.

17) The observed CD spectrum has been corrected to optical and isotopicalpurity18.

18) For 11 we recorded £cT]q+66.5 (abs. Et0H)j Mattinen found[a] +73.94° (EtOH). Assuming his value19 to be correct20, our producthas an optical purity of 89.9%. The correction factor applied to theobserved spectrum was 10000/89.9*30.08, where 30.08 stands for theisotopical purity.

19) V. Mattinen, Ann. Acad. Sci. Fennicae, All 105. 22 (1961).20j Although we started the synthesis with optically pure camphor, we

cannot exclude racemisation because racemisation of norbornane

48

derivatives sometimes occurs very easily. Cf. the oxidation ofoptically active norborneol (J.A. Berson, J.S. Walia, A. Romanic,S. Suzuki, P. Reynolds-Warnhoff and D. Willner, J. Amer. Chem. Soc.,83, 3906 (1961)), and the decomposition of epi-isoborneol-tosylateon column chromatography (W.Z. Antkowiak, Bull. Acad. Pol. Sci., Ser.Sci. Chim., _14, 431 (1966)).

21) The absolute configurations follow from the known absolute con­figuration of camphor, cf. M.G. Northolt and J.H. Palm, Rec. Trav.

Chim., j j, 143 (1966).) We borrowed the idea to use IM-methylmorpholine as a solvent in LAH

reductions from: R.R. Sauers and J.A. Wittle, J. Qrg. Chem.,34. 3579 (1969).

23) Org. Synth., vol. 45, 12, 14, 55.21*) Ref. 23), p 55.25) T. Kuusinen, Suomen Kemistilehti, Bj31_, 179, 356 (1950).26) Org. Synth., vol. 29, 24.27) Y. Asahina, fl. Ishidate and T. Sano, Ber., 69, 347 (1936).28) P. Wilder, Jr., and A. Winston, J. Amer. Chem. Soc., 7 5, 5370 (1953).

) W.C. Fong, R. Thomas and K.V. Scherer, Jr., Tetrahedron Letters,(1971) 3709.

30) C.V. Wilson, Org. Reactions, vol. 9, 332.31) W.C. Evans, J.M, Ridgion and J.L. Simonsen, J. Chem. Soc., (1934) 137.32) A.L. Brady, J. Chem. Soc., (1931) 756.33) There seemed to be a large isotope effect in the reduction of 3: under

conditions where LAH reduction of _3 was complete, LAD gave a mixtureof the desired alcohol 4) (minor product) and 1-bromo-a-fencho-camphorol. But we have not investigated whether this result of LADreduction is reproducible.

) We have not investigated why the deuterium content of _5 and £ was muchlower than was expected.

% % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % %

49

CHAPTER FOUR

A COMPARISON OF ELECTRONIC SPECTRA OF SOME NORCAMPHORQUINONES ■

Hug & W agnière and Charnsy 8 T s a i1 have assumed th a t th e no rbo rnane

s k e le to n in cam phorquinone i s tw is te d , i . e . a c c o rd in g to them th e bonds

C^-Cg and C,--Cg in cam phorquinone a re n o t in th e same p la n e .

We lo o ke d f o r e x p e r im e n ta l e v id e n ce c o r ro b o ra t in g t h i s p o s tu la te by

com paring th e s p e c tra o f a number o f s u b s t i t u te d no rcam phorqu inones. The

id e a u n d e r ly in g o u r approach was, t h a t i f a s m a ll s u b s t i tu e n t such as th e

b r id g e head m e th y l group in cam phorquinone was s u f f i c ie n t t o cause t w is t

in th e no rbo rnane s k e le to n o r t o s h i f t a c o n fo rm a tio n a l e q u i l ib r iu m

between tw is te d c o n fo rm e rs , th e n a b u lk ie r g roup a tta c h e d t o th e s k e le to n

in a w e l l chosen p o s i t io n m ig h t in c re a s e th e e f f e c t and a c c o rd in g ly

enhance th e r o ta to r y s t re n g th s o f th e e le c t r o n ic t r a n s i t i o n s in th e re g io n

250-520nm. A lth o u g h th e in t r o d u c t io n o f t . - b u t y l g roups was d e s ir a b le , o u r

e x p e r im e n ta l e f f o r t s were d i r e c te d t o more e a s i ly a c c e s s ib le compounds.

A l l o f th e th re e p re p a re d 7 ,7 -d im e th y l-n o rc a m p h o rq u in o n e s showed an i n ­

c rea se o f r o t a t o r y s t re n g th o f b o th bands as compared w ith cam phorquinone

( f i g . 4 - 1 ,2 - ? ) ) . The a b s o rp tio n cu rve s o f th e s e compounds in th e v is ib le

re g io n a re d is p la y e d in f i g . 4 -3 . F o r com parison th e a b s o rp tio n cu rve o f

is o fe n c h o n e q u in o n e has been added ( f i g . 4 - 4 ) .

Data o f e le c t r o n ic s p e c tra c f some no rcam phorqu inones.

compound s o lv e n t UV-band v is i b le band m id p o in t3A e e Ae . _max max min

6 -e nd o -a ce to xy -ca m p h o rq u in o n e CHCl^ + 1 .9 3 46 .1 -1 .1 9 4 8 7 .1nm1-b rom o-o -fenchocam pho ronequ inone " + 1 .14 53 .9 -2 .9 7 4 6 2 .7nm5 -e xo -a ce to xy -ca m o h o rq u in o n e * +0.55 52 .2 -0 .6 6 4 9 5 .7nmcam phorquinone " ♦0 .40 42 .9 -0 .4 7 4 8 9 . 6nm

" i . o c t . +0 .27 36 .7 -0 .4 3 4 9 1 .8nmis o fe n c h o n e q u in o n e C6H12

+0.93 45 .0 -0 .4 0 5 0 2 .3nma-fenchocam phoronequ inone 39. B 491.7nm

" CHgCfj 36 .9 4 8 7 .2nm

i . o c t . = is o -o c ta n e C_H =b izcyc lohexane

I f , f o l lo w in g Hug & W agnière and Cham ey g T s a i, we make th e

s im p l i f y in g assum ption t h a t o n ly th e d ih e d r a l a n g le o f th e a - d ic a rb o n y l

chrom ophore d e te rm in e s th e m agnitude o f th e e f f e c t in CD and th e p o s i t io n

o f th e a b s o rp tio n bands, th e n we e xp e c t t h a t in c re a s e o f th e d ih e d ra l

a n g le o f th e chrom ophore s h o u ld be accom panied by an in c re a s e o f r o ta to r y

s t re n g th o f b o th bands and by a decrease o f th e w a ve le ng th o f th e

50

zo

F ig u re 4-1

F ig u re 4 -2

51

Figure 4-3 To allow a better comparison of the band shapes theseabsorption curves have been normalized. The same wasdone with the curves in the next figure. For the actualvalues of s of these compounds cf. the table on p 50.max

£•( scale factor) in cyclohexane

in iso-octane

Figure 4-4

Figure 4-5H

52

absorption maximum at least of the visible band1*.It is seen from the spectra (fig. 4-1,2,33 that this assumption is too

simplistic: compound C, which absorbs at the longest wavelength, has notthe smallest value of Ae in both bands: compound B, which absorbs at theshortest wavelength, and thus might have the largest twist in its skeleton,has only in the visible region a larger effect in CD than any of the otherdiketones.

However, the most conclusive evidence against the idea that a twistedct-dicarbonyl group is necessary to explain the observed optical activityof a-diketones is the occurence of a bisignate CD curve in isofenchone-quinone (fig. 2-3). This cannot be explained by the theories1. It might beexpected that a theory involving vibronic coupling will be necessary toaccount for the spectra of norcamphorquinones, just as such an approach hasbeen necessary for the explanation of CD curves of norbornanones5 6.

Although the prediction of the sense of twist present in camphorquinone,made by Charney & Tsai on the basis of their calculations, agrees withresults from X-ray analysis1, we do not consider this agreement as a con­vincing proof for the justification of their model. In view of thediscussion of our experimental results we are inclined to consider thisagreement as rather fortuitous7. Therefore a choice between thecontroversial views held by Hug & Wagnière at the one hand and by Charney& Tsai at thB other hand, concerning the splitting of the two n-levelsin a-diketones, is still not possible. The synthesis of large ringa-diketones (such as in fig. 4-5) of known absolute configuration and thusof known sense of twist in the chromophore may help to settle this question.

Experimental.Melting points are not corrected, angles of rotation were measured with aBendix-NPL photoelectric polarimeter, or with a Perkin-Elmer polarimeter(model 141) at room temperature. NMR shifts are with respect to TMS.6-Endo-acetoxy-camphorquinone (A, fig. 4-1,2,3). For its preparation seein chapter 5 the experimental section concerning 2,6-diketocamphane.NMR data (CC1 ): three methyl groups at 6=0.946, 1.137, 1.174ppm (thesemethyl peaks only have bBen measured in CDCl„)j H attached to C^ (bridgehead): quartet, 6=1.516ppm, J =14.5Hz, J2=3.0Hzj H attached to Cg: octuplet,6=5.105ppm, J =9.6Hz, J2=3.0Hz, J3=1.1Hz.1-Bromo-a-fenchocamphoronequinone (B, fig. 4-1,2,3) is described in

53

chapter 3.The classical synthesis of isofenchonequlncne [fig. 4-6)

«Fr* ©Figure 4-6 SeOg

O x id a tio nJones

HO

O H ~

AcO

8 7 6 5

(-)-a-Fenchene (40 was prepared from (+)-fenchone (1). See chapter 2.Isofenchylacetate (jj) was prepared from 4 according to Wallach8.Isofenchol (6) was prepared from 5 by saponification8. Yield 79%based on 4Isofenchone [7]. Jones oxidation of 6, analogous to the preparation ofnorcamphor from norborneol8, gave 7 in 60% yield. After purification asthe semicarbazone, mp 222-3°, o] -12.6° (MeOH), (recrystallised fromalcohol), (lit.8: mp 221-2°, £a]p-8.27° (MeOH)), the Ketone had[a]p-28.5° (MeOH). No specific rotation of 7 in MeOH was to be found inthe literature. Rassat18 only gives ORD data in MeOH.Isofenchonequinone (ji). 7_ (3.0g, purified as the semicarbazone) wasoxidized with selenium dioxide in acetic anhydride11. To the reactionmixture was added dichloromethane, it was filtered and washed withNaHCO. solution till neutral. The red colour could not be removed byfiltering through silica gel. Then the solvent was removed and theresidue distilled. The distillate was purified by prep. G.L.C. (SE-30column). Yield 0.8g, mp 68.5-71.0°, [a]^-4.0±0.5° (cyclohexane). Lit.18:mp 65 . There does not seem to be a reliable value for the specificrotation of j) in the literature. Some Russian authors, referred to by18), give a specific rotation of J3 but they do not give the solvent usedfor this measurement. Rassat18 gives ORD data (cyclohexane), but a valueof extrapolated from these ORD data is much higher than we haverecorded; Rassat also gives an absorption curve (cyclohexane), but inthe visible region his value of e (=77) is much higher than we havefound (e =45.0). Only when we calculated the contribution of the CDband in thB visible region to the ORD12 (fig. 4-7) a reasonable agree­ment of the corresponding part of the ORD curve of Rassat was found

max

54

800

in cyclohexane

( I S ) - IS0FENCH0NEQUIN0NE

-600-

Figure 4-7 Calculated contribution of the CD band of isofenchone-quinone to the ORD.

NaNH;_R-0N0

9I t10

0 NH,OHNaCIO

^NOH

Figure 4-0

SeO; (if* , HAca (Ac)20 h2s0*4co o Aco

U 13

(shape, amplitude). Calculated amplitude 1351°; Rassat10 gives 1385°.The synthesis of 5-exo-acetoxy-camphorquinone (fig. 4-8)13.

Isonitrosocamphor (10) was prepared from (+)-camphor (BDH) analogousto ***).q-Diazocamphor (1_1_) was prepared from using the Forster reaction15.e-Pericyclocamphanone (12). Cf. 16). A round-bottomed lOOml-flaaK.provided with a condenser and containing (5g) and copper bronze(7.5g) is placed in an oil bath. The temperature of the bath is slowlyraised to 120°. At a temperature of about 110° 11 decomposes. Theproduct is isolated either by sublimation from the flask or byscratching from the condenser. Yield 78%. The product (12) containsabout 1% of _11_ as an impurity.

55

5 -E x o -a c e to x y -c a n p h o r [ 13) was p re p a re d by a d d it io n o f a c e t ic a c id t o 12/

in th e manner o f T a k e u c h i17. A f t e r th e re a c t io n th e m ix tu re was steam

d i s t i l l e d . The f i r s t f r a c t io n c o n s is te d o f u n re a c te d 12 t h a t co u ld be

used a g a in ; th e second f r a c t io n o f th e d i s t i l l a t e was a l i q u i d m ix tu re

o f th e re a c t io n p ro d u c ts and s t a r t in g m a te r ia l , w h ich c o u ld be s e p a ra te d

by p re p . G .L .C . [H I-E FF co lu m n ). From 12_ ( 2 7 .5g) was th u s o b ta in e d 3 .7 g

o f c rude r e a c t io n p ro d u c t [ an 1 :4 m ix tu re o f tw o is o m e rs ) , whereas 7 .0 g

o f 12 , mp 1 6 3 -5 ° c o u ld be re c o v e re d . We were unab le t o p u r i f y 13, by

c r y s t a l l i s a t io n because o u r e f f o r t s t o i n i t i a l l i z e c r y s t a l l i s a t io n o f

13 were n o t re w a rd in g .

5 -E xo -a ce to xy -ca m p h o rq u ln o n e (1 4 ) . T o iv o n e n 's p ro c e d u re 18 f o r th e

o x id a t io n o f 6 -e x o -a c e to x y -e p ic a m p h o r was used. The r e a c t io n p ro d u c t o f

crude 13 (3 .7 g ) and s e le n iu m d io x id e was f i l t e r e d a f t e r CH2 C12 had been

added, and th e n washed w ith NaHC03 s o lu t io n t i l l n e u t r a l . A n a ly t ic a l

s e p a ra tio n (G .L .C .) o f th e components o f th e m ix tu re was p o s s ib le u s in g

a HI-EFF colum n. Two d ik e to n e s were fo rm ed b u t th e main p ro d u c t co u ld be

o b ta in e d pu re by r e c r y s t a l l i s a t i o n (4x ) fro m hep tan e . Y ie ld 1 .5 g , mp

9 1 -2 ° , [ a ] D-1 4 2 ° (C H C lg). L i t . 19 : mp 9 2 -3 ° , [ a ] D-1 3 6 ° (CHC13) .

NMR d a ta (CC1 ) : th re e m e th y l groups a t 6 = 0 .9 0 6 , 1 .1 1 4 , 1.259ppm; H

a tta c h e d t o C. (b r id g e h e a d ): u n s p l i t peak a t 5=2.828ppmj H a tta c h e d to

CL: q u a r te t , 6=4.917ppm, J ,|=7 .1H z, J 2 =4.3H z.

R e fe re n c e s .

1) W. Hug and G. W agn iè re , H e lv . Chim. A c ta , 5 4 , 633 (1 9 7 1 ).

E. Cham ey and L. T s a i, J . Amer. Chem. S o c . , £ 3 , 7123 (1 9 7 1 ).

In b o th p u b l ic a t io n s i t i s assumed th a t th a s k e le to n o f cam phorquinone

i s tw is te d , b u t th e re i s d isag reem en t as t o th e sense o f t w i s t . From

X -ra y a n a ly s is ( L .T s a i , E . C harney, J .V . S i lv e r t o n and W.M. B r ig h t , t o

be p u b lis h e d ) i t has been con c lu ded t h a t th e sense o f t w is t advoca ted by

Cham ey & T s a i i s c o r r e c t , a t le a s t in th e s o l id s ta te .

2 ) The a b s o lu te c o n f ig u r a t io n s o f th e compounds a re d e p ic te d in th e

f ig u r e s .3) The shape o f th e to p o f th e a b s o rp tio n cu rve s o f a -d ik e to n e s in th e

v is i b le re g io n i s r a th e r i r r e g u la r . The in te r s e c t io n o f th e l in e

e (X )= ie w ith th e a b s o rp tio n cu rve in th e v i s ib le re g io n a t lo n g e s tmax

w a ve le ng th i s more c h a r a c t e r is t i c th a n th e a b s o rp tio n maximum f o r t h i s

a b s o rp tio n band. T h e re fo re we g iv e th e w a ve le ng th o f t h i s p o in t , t o be

56

called a midpoint, in the table. Midpoints are indicated in fig. 4-3.) Indeed it has been shown (in spectra of large ring ot-diketones] that

increase of the dihedral angle in the chromophore is accompanied by adecrease of the wavelength of the absorption maximum in the absorptionband at longest wavelength. Cf. N.J. Leonard and P.M. Mader, J. Amer.Chem. Soc., £2. 5388 (1950).

5) For CO curves of unusual shape of norbornanones see:C. Coulumbeau and A. Rassat, Bull. Soc. Chim. Fr., (1963) 2673,

(1966) 3752.D. E. Bays, G.W. Cannon and R.C. Cookson, J. Chem. Soc. B, 885 (1966).The CD band of thiocamphor in the visible region is not well-behavedeither, cf. C.A. Emeis, Thesis Leiden (1968), p110.

°) For theory on the CD of norbornanones see:R.T. Klingbiel and H. Eyring, J. Phys. Chem., 74, 4543 (1970).

7) Every theory, however poor, has a probability of 25% to predictcorrectly the sign of two Cotton effects as in camphorquinone.

8) 0. Wallach, Ann., 362, 191 (1909).8) J .A. Berson, J.S. Walia, A. Remanick, S. Suzuki, P. Reynolds-Warnhoff

and D. Willner, J. Amer. Chem. Soc., 83, 3986 (1961).10) H.-P.- Gervais and A. Rassat, Bull. Soc. Chim. Fr.. (1961) 743.n ) W.C. Evans, J.M. Ridgion and J.L. Simonsen, J. Chem. Soc., (1934) 137.12) C.A. Emeis, L.J. Oosterhoff and Gonda de Vries, Proc. Roy. Soc.,

A297, 54 (1967).13) This part of the work was done in cooperation with Mr. F.A. Varkevisser.1‘*) J. Bredt and W.H. Perkin, J. Chem. Soc., 103, 2290 (1913).15) Houben-Weyl, Methoden der Organischen Chemie, Georg Thieme Verlag

Stuttgart, Bd 10/4, pp 583-4 (1968).16) J. Bredt and W. Holz, J. Prakt. Chem., n.F. 95 , 148 (1917).17) K. Takeuchi, Sci. Pap. Inst. Phys. Chem. Res. Tokyo, 25, 69 (1934).18) J. Toivonen and A. Halonen, Suomen Kemistilehti, B19, 1 (1946).

Cited after Chem. Zentr., (1946) I, 2393.19) A. Marquet, M. Dvolaitzky and D.' Arigoni, Bull. Soc. Chim. Fr.,

(1966) 2956.

% % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % %

57

CHAPTER FIVE

TWO SYNTHESES OF OPTICALLY PURE M R :2R)-1,2-DIMETHYLCYCLOPENTANE.W.C.M.C. Kokke and F.A. Varkevisser,Department of Theoretical Organic Chemistry, University of Leiden.

Summary.Two syntheses of optically pure MRs2R)-1,2-dimethyloyolopentane aredescribed. In the first synthesis (+)-pulegone was converted into2,3-dirnethylcyclopentanone whose semicarbazone on Wolff-reduction affordeda mixture of the title compound and meso-1,2-dimethylcyclopentane. In thesecond synthesis the title compound was prepared from 3,4-dimethylcyclo-pentanone which was synthesized from resolved 4-cyclohexene-1,2-dicarboxylic acid. The specific rotations found for the hydrocarbon wererespectively [a] -49.7° and -51.5° (CHClg), in disagreement with aliterature value of -35 .

Introduction.Recently optically active trans-1,2-dimethylcyclopentane has been

discovered in a crude oil1. The specific rotation found was 5.6 but atheoretical estimate made many years ago in this department resulted in amuch higher value^. Therefore it became of interest to synthesize thissubstance. When we had completed the synthesis from (+)-pulegone (fig.5-13

(The absolute configurations of the compounds are depicted in the figures )

P.0. Box 75. Leiden, The Netherlands.

Fig. 5-1

6,7 (ShtC5l| 0 COOH \\

ö < - c$<COOH \\ „

58

we became aware o f a pape r by H i l l , e t . a l . 3 w h ich we had o v e r lo o k e d b e fo re .

In t h e i r w ork on th e a b s o lu te c o n f ig u r a t io n o f th e a n t ib io t ic u m sa rcom yc in

th e y a ls o p re p a re d t ra n s -1 ,2 -d im e th y lc y c lo p e n ta n e fro m ( + ) -p u le g o n e , b u t

by a ro u te d i f f e r e n t fro m o u r ro u te ( f i g . 5 -2 ) . T a k in g a b s o lu te v a lu e s .

NaOC?HsCOOC2Hs “ “ COOH

1) 032) Li A l H4

[5. nmiCH2OTs «"'CH2OH

F ig . 5-2 H i l l ' s s y n th e s is o f d im e th y lc y c lo p e n ta n e 3 .

th e an g le o f r o t a t io n we found was 42% h ig h e r tha n th e h ig h e s t v a lu e

re p o r te d by H i l l 3 . T h e re fo re i t became o f im p o rta n c e t o fo l lo w a second

ro u te t o th e same su b s ta n ce .

The ro u te we chose was an o b v io us e x te n s io n o f a s y n th e s is used by

W a lb o rs k i, e t . a l . 3 f o r th e d e te rm in a t io n o f th e a b s o lu te c o n f ig u r a t io n o f

re s o lv e d 4 -c y c lo h e x e n e -1 ,2 -d ic a rb o x y lic a c id ( f i g . 5 - 3 ) . B oth syn th eses

^ X O O H - v x h 2oh

^ ^ * * 'ch2oh

^ - s^ C H j OTs

^ ^ C H 2OTs

H Q O C y ^ s

HO O C ^^NIt

°=<X-cC19 20

F ig . 5 -3

le d to compounds w ith n e a r ly id e n t i c a l va lu e s o f th e a n g le o f r o t a t io n .

T h e re fo re i t can be s ta te d t h a t th e s p e c i f ic r o t a t io n o f o p t i c a l l y pu re

(1 R :2 R )-1 ,2 -d im e th y lc y c lo p e n ta n e i s £ a |_ -5 1 .5 0 (CHC1_).

D im e th y lc y c lo p e n ta n e fro m pu legone ( f i g . 5 ~ 1 ).

P ulegone was h y d ro ly s e d to g iv e 3 -m e th y lc y c lo h e x a n o n e . The 6 - p o s i t io n in

t h is ke to ne was b lo c k e d by c o n d e n s a tio n w ith benza lde hyd e , y ie ld in g

a -b e n z y lid e n e -k e to n e ° . M e th y la t io n o f t h i s compound gave a m ix tu re o f

mono- and d i-m e th y la te d p ro d u c t, to g e th e r w ith u n re a c te d a -b e n z y lid e n e -

ke to n e . O x id a t io n o f t h i s m ix tu re and d e c a rb o x y la t io n o f th e a c id s o b ta in e d

y ie ld e d a m ix tu re o f 3 -m e th y lc y c lo p e n ta n o n e , 2 , 3 -d im e th y lc y c lo p B n ta n o n e

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2,2,3-trimethylcyclopentanone. The Ketones were separated by distillation.The semicarbazone of 2,3-dimethylcyclopentanone gave on Wolff-reduction amixture of optically active and meso dimethylcyclopentane [83.3 : 16.7%).Corrected to chemical purity trans-1,2-dimethylcyclopentane showedTal -49.7° (CHC1„). Hill3 reported fal -35° (CHC1,). In the course of thisl j d 3 LJ oinvestigation it became also of interest to study possible epimerisationduring Wolff-Kishner-reductions. The results are described in theexperimental section.

Dimethylcyclopentane from 4-cyclohexene-1,2-dicarboxylio acid [fig. 5~3)■Two steps in Walborski’s synthesis of 3,4-dimethylhexanedioic acid5 couldbe improved.

We recommend N-methylmorpholine7 as a solvent for the preparation oflow-molecular-weight hydrocarbons by LAH-reduction of sulphonic estersthe hydrocarbon is easily obtained pure and in high yield when the reactionmixture is worked-up by steam distillation®.

The resolution of 4-cyclohexene-1.2-dicarboxylic acid wasreinvestigated. It was found that the best results are obtained whenquinidine is used.

The angle of rotation of 3,4-dimethylcyclopentanone ([oQD-241° (CHClg))appeared to be much higher in absolute value, than was recorded byCarnmalm® (£ajg-160° (CHClg))j in contrast the angle of rotation of thecorresponding semicarbazone was found to be in reasonable agreement withhis results.

We also tried to resolve racemic 3,4-dimethylcyclopentanone with theWoodward reagent "menthydrazide"*®, but our efforts were not rewarding.

Experimental.Melting and boiling points are not corrected. Angles of rotation weredetermined with a Bendix-NPL photo-electric polarimeter, or with aPerkin-Elmer polarimeter (model 141) at room temperature.Pulegone (1_) was isolated from pennyroyal oil (Dragoco, Holzminden,W. Germany) as the sodium bisulphite adduct**, prepared at pH=7. Afterdistillation over an efficient column it had Q>Qq+23.8 (MeOH).(3R) -3-Methy lcyclohexanons (2_), |a| p+8.60 (MeOH), was prepared byhydrolysis of 1_ in 65% yield*7.

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C3R)-3 -M e th y l-6 -b e n z y lid e n e -c y c lo h e x a n o n e C^l was p re p a re d by W a lla c h 13 by

co n d e n sa tio n o f 2_ w i th benza ldehyde in a lc o h o l. To p re v e n t th e fo rm a t io n o f

d ib e n z y lid e n e -k e to n e i t i s c o n v e n ie n t to use w a te r in s te a d o f a lc o h o l11*.

A m ix tu re o f 2_ (1 5 2 g ), benza ldehyde (152g) and 4% K O H -s o lu tio n (1520g) was

v ig o ro u s ly b o i le d f o r th re e h o u rs . A f t e r n e u t r a l iz in g th e u n re a c te d ke tone

and a ldehyde were removed by steam d i s t i l l a t i o n . The y e l lo w re s id u e in th e

steam f la s k c r y s t a l l i s e d on c o o lin g in ic e . The c rude p ro d u c t was d i s t i l l e d

and th e d i s t i l l a t e r e c r y s t a l l is e d fro m p e tro le u m e th e r to g iv e 208g =72.5%

o f 3 , mp 6 1 .5 - 3 .0 ° . [a J D-1 5 1 .6 ° (MeOH) a f t e r r e c r y s t a l l i s a t i o n from

THF-hexane. Racemic 3, p re p a re d in th e same manner fro m ra c . 2_ (F lu k a )

had mp 3 8 -4 1 ° .

M e th y la t io n o f 3 . A f te r v a r io u s a tte m p ts on th e b a s is o f th e p ro ced u re o f

W.S. Johnson13 f o r th e m e th y la t io n o f 2 -m e th y l-6 -b e n z y lid e n e -c y c lo h e x a n o n e

i t was found th a t th e fo l lo w in g p ro ce d u re gave th e h ig h e s t y ie ld o f

d i s t i l l a b l e re a c t io n p ro d u c t.

In a 2 1 - f la s k , p ro v id e d w i th an e f f i c i e n t s t i r r e r 16, po ta ss iu m (2 3 .Og) was

d is s o lv e d in t e r t . - b u t a n o l ( 1 i l , d r ie d on s ie v e s ) under n i t r o g e n . T h is

s o lu t io n was p la c e d in an i c e - s a l t m ix tu re , and when i t was c o o le d to 22

a s o lu t io n o f ^ MOOg) in m e th y l io d id e (213g) was added a t once. The

te m p e ra tu re the n rose to 3 1 -4 ° . When th e m ix tu re was co o le d to 25 , th e

b a th was removed and th e s o lu t io n was r e f lu x e d f o r 1£ h o u rs , th e n th e

s o lv e n t was removed w ith s u c t io n s w a te r and e th e r were added to th e re s id u e .

P a r t o f th e re a c t io n p ro d u c t th e n c r y s t a l l i s e d . These c r y s ta ls had mp

1 0 1 .0 -2 .5 ° , £eQ0 -7 0 .5 ° (MeOH), a f t e r r e c r y s t a l l i s a t i o n fro m hexane and

e th e r . I t was fou nd t o be (mass s p e c tro s c o p y ) a lm o s t pure

(3 R )- 2 , 2 , 3 - t r im e th y l-6 -b e n z y lid e n e -c y c lo h e x a n o n e (5^), th e im p u r it y b e in g

a few p e rc e n t (3 R )- 2 , 3 -d im e th y l-6 -b e n z y lid e n e -c y c lo h e x a n o n e (4 K The p a r t

o f th e re a c t io n p ro d u c t w h ich d is s o lv e d in e th e r was d i s t i l l e d . Y ie ld

( d i s t i l l a t e + c r y s ta ls ) 68g. Mass s p e c tro s c o p y showed 5_ to be th e main

p ro d u c t) th e re was more s t a r t in g m a te r ia l 3 in th e m ix tu re th a n mono-

m e th y la te d p ro d u c t 4 , w h ich i s n o t s u r p r is in g because C o n ia17 has shown an

a -a lk y 1 -k e to n e to be more r e a c t iv e in a lk y la t io n th a n a ke tone w ith o u t an

a - a lk y l g roup .

O x id a t io n o f th e m e th y la t io n p ro d u c ts . The p ro ce d u re o f W.S. Johnson1 f o r

th e o x id a t io n o f c is -2 -b e n z y lid e n e -9 -m e th y ld e c a lo n e was used. In o u r case

th e w o rk in g -u p was s im p le because th e m e th y l- s u b s t i tu te d a d ip ic a c id s 6 , 7_,

61

and 8 a re much b e t te r s o lu b le in w a te r tha n b e n z o ic a c id , and most o f th e

la t t B r c o u ld be removed by f i l t r a t i o n . 3_ (450g) gave a f t e r m e th y la t io n and

o x id a t io n a m ix tu re o f 6^ 7_ and 8_ (1 7 5 .5g, a d a rk brown o i l ) .

A m ix tu re o f cyc lo pe n tan one s 9 , 10 and 11 (7 4 .6 5 g ) was p repa red by h e a t in g

th e c rude m ix tu re o f d ic a r b o x y l ic a c id s 6_, 7_ and 8 (1 7 5 .5g) w ith Ba(OH) 19.

The ke tones were s e p a ra te d by d i s t i l l a t i o n , u s in g a N e s te r-F a u s t s p in n in g

band co lum n, to y ie ld £ , 7 .8 g , b p ^ 106°; 10 , 3 .6 g , b p ^ j . 1 1 5 -7 °; 11 ,

2 0 .4g, bp175 1 2 4 -5 ° .

(3 R )-3 -M e th y lc y c lo p e n ta n o n e (9 ^ , bp 1 4 4 -6 ° , Qx] + 154 .8 ° (MeOH), was

p re p a re d by o z o n is a t io n 26 o f 1 to g iv e (3 R )-3 -m e th y lh e x a n e d io ic a c id (6^ ,

d e c a rb o x y la tio n w ith B a (0H )_19, and p u r i f i c a t i o n as th e sem icarbazone,

mp 1 7 1 -3 ° , | j* lg + 4 0 .5 ° (C H C l^). C o rro b o ra t in g T é t r y ’ s r e s u l t 6 we found f o r

th e m e th y lc y c lo p e n ta n o n e f r a c t io n o f th e d i s t i l l a t i o n o f th e m ix tu re o f

9 , 10 and 11 p h y s ic a l c o n s ta n ts in agreem ent w ith th e d a ta o f t h is

re fe re n c e , p re p a re d by o z o n is a t io n o f 1_ e t c . .

(3R )- 2 , 2 , 3 -T r im e th y lc y c lo p e n ta n o n e (1 1 ) , bp 1 6 2 -4 ° , £aJp+79.6° (MeOH),

w h ich has n o t been d e s c r ib e d b e fo re , was o b ta in e d by p u r i f i c a t i o n o f th e

c o rre s p o n d in g f r a c t io n o f th e d i s t i l l a t i o n o f th e m ix tu re o f 9_, W. and Ü

as th e sem icarbazone, [a ] + 2 4 .1 ° (CHC1 ) . T h is sem icarbazone

( r e c r y s t a l l is e d fro m a lc o h o l) tu rn s y e llo w a t 2 1 0 ° j on ra p id h e a t in g

mp 2 1 6 -8 ° i s fo u n d .

(2 R ) -1 ,1 ,2 -T r im e th y lc y c lo p e n ta n e ( 13) . U s ing th e c o n d it io n s o f

K o h lra u s c h 21 f o r th e re d u c t io n o f 3 -m e th y lc y c lo p e n ta n o n e -s e m ic a rb a z o n e ,

th e sem icarbazone o f 11 gave 13 on W o lf f - r e d u c t io n . We always w orked-up

re a c t io n p ro d u c ts o f W o lf f - r e d u c t io n s by steam d i s t i l l a t i o n , s h a k in g th e

up pe r la y e r o f th e d i s t i l l a t e w ith an e q u a l volume o f cone. H2 S0 ^ , w ash ing

w i th w a te r , d r y in g on and d i s t i l l a t i o n from sod ium . J_3 was found t o be

c o n ta m in a te d w ith 2 .3 2 mole% o f ( - ) - 1 2 and 0 .4 8 mole% o f meso-12.

C o rre c te d to che m ica l p u r i t y J_3 had -8 .0 7 ° (C H C l^). Y ie ld 66%.

(1 R :2 R )-1 ,2 -D im e th y lc y c lo p e n ta n e [ ( - ) - 1 2 ) . The sem icarbazone o f 10,

p re p a re d fro m th e c o rre s p o n d in g f r a c t io n o f th e d i s t i l l a t i o n o f 9 , ^0_ and

11, a f t e r r e c r y s t a l l i s a t i o n fro m a lc o h o l, had Q xjp+94 .1° (C H C l^), mp

2 0 0 -2 ° i th e c r y s ta ls tu r n y e l lo w between 195 and 200 . R e d u c tio n 21 o f t h is

sem icarbazone gave ( - ) - 12 , co n ta m in a te d w i th 1 6 .3 mole% o f meso-12, 1.52

mole% o f 13 and 0 .4 0 mole% o f m e th y lc y c lo p e n ta n e in 59% y ie ld . C o rre c te d

to ch e m ica l p u r i t y ( - ) -12 had JjqQ _ -4 9 .7 ° (C H C l^).

Rac. t r a n s - 4 - c y c lo h e x e n e - 1 ,2 - d ic a r b o x y l ic a c id ( ra c . 1 4 ) . The D ie ls - A ld e r

62

adduct fro m d ie th y lfu m a ra te (M erck) and b u ta d ie n e was s a p o n if ic a te d to

g iv e ra c . _14_, mp 1 6 6 .0 -0 .5 ° a f t e r r e c r y s t a l l i s a t i o n fro m w a te r .

R e s o lu t io n o f t r a n s - 4 - c y c lo h e x e n e - 1 ,2 - d ic a r b o x y l ic a c id (1 4 ) . W a lb o rs k i's

p ro c e d u re 5 f o r th e r e s o lu t io n o f _1_4 is cumbersome, and th a t was f o r us an

inducem ent to r e in v e s t ig a te th e r e s o lu t io n . Bases used were e p h e d r in e ,

q u in in e 2 2 , s t r y c h n in e , b ru c in e , c in c h o n id in e , c in c h o n in e and q u in id in e .

The l a t t e r gave th e b e s t r e s u l t s .

- P re p a ra tio n o f th e q u in id in e s a l t . In a 1 1 - f la s k i s r e f lu x e d t i l l

homogeneous anhydrous q u in id in e (B rocades, The Hague, The N e th e r la n d s , o r

D r. Lamers & D r. Indemans N .V . , B o is - le -D u c , The N e th e r la n d s ) (8 1 g ), 14

(2 1 .2g) (2 m oles o f a lk a lo id : 1 mole o f _14) and a lc o h o l (5 0 0 m l). In th e

case th e m ix tu re is n o t homogeneous a f t e r 30 m in u te s , i t i s f i l t e r e d . The

a lc o h o l i s removed w ith a r o ta to r y e v a p o ra to r , and to th e re s id u e i s added

w a te r (500m l) and a lc o h o l (1 5 0 m l) ; on h e a t in g a c le a r s o lu t io n i s o b ta in e d

w h ich i s l e f t t o c o o l. E very t im e when i t becomes t u r b id th e t u r b i d i t y is

removed by th e a d d it io n o f some a lc o h o l (ab ou t 60ml o f a lc o h o l is

n e c e s s a ry ). Seeding is recommended. A f t e r s ta n d in g f o r two days a t room

te m p e ra tu re th e c r y s ta ls a re f i l t e r e d o f f and a re r e c r y s t a l l is e d . We used

w a te r (6 .5 1 ) and a lc o h o l (2 .5 1 ) f o r th e r e c r y s t a l l i s a t i o n o f q u in id in e

s a l t fro m (292g) and q u in id in e (1 1 2 0 g ), seeded, l e f t t o c r y s t a l l i s e f o r

two days, and o b ta in e d 4 8 6 .25g o f s a l t .

- R e ge ne ra tion o f th e q u in id in e s a l t . R e c r y s ta l l is e d q u in id in e s a l t (108g)

was s t i r r e d w ith CHClg (340m l) and a s o lu t io n o f NaOH (20g) in w a te r

(120m l) f o r 1 .5 h o u r. Then th e CHC1 - la y e r c o n ta in in g th e a lk a lo id was

s e p a ra te d fro m th e a lk a l in e la y e r c o n ta in in g th e sodium s a l t o f (1 R :2 R )-1 4 .

The l a t t e r s o lu t io n was a c id i f ie d w i th cone, h y d r o c h lo r ic a c id , and th e

d ic a r b o x y l ie a c id was is o la te d by e th e r e x t r a c t io n . From q u in id in e s a l t

(4 8 6 .25g fro m 292g o f ra c . 1_4) was th u s o b ta in e d (1R :2 R )-24 (9 8 .Og =67.1%

o f one a n t ip o d e ) , [ a ] D-1 6 1 ° (ab s . EtOH). L i t . 5 : [a ] -1 6 1 ° (a b s . E tO H ).

- The m o th e r - l iq u o r o f th e r e s o lu t io n o f T4 (292g) w ith anhydrous

q u in id in e (1120g) was e va p o ra te d t o d ryness to g iv e an o i l , w h ich was

t re a te d w ith NaOH s o lu t io n and CHCl^ e tc . as in d ic a te d above t o g iv e

o p t i c a l l y im pure (1 S :2 S )-2 4 (1 6 6 .5 g ) , [c t] D+90° (ab s . EtOH).

- Q u in id in e can be re co ve re d in h ig h y ie ld by e v a p o ra t in g i t s CHClg-

s o lu t io n s t o dryness and r e c r y s t a l l i s i n g th e re s id u e fro m MeOH ( ^ O g o f

a lk a lo id : 11 o f MeOH).

( 1R :2R )- 4 -C y c lo h e x e n e -1 ,2 -d im e th a n o l (15_) was p re p a re d by LAH re d u c t io n o f

63

(1 R :2 R )-1 £ in THF in 94% y ie ld .( 1R: 2R) -4 -C yc loh exe ne ,-1 , 2 -d im e th a n o l- d i t os y la te ( 16) was p re pa red fro m 1_5

w ith .A .R . p . - to lu e n e s u lp h o n y lc h lo r id e in A.R . p y r id in e . Y ie ld 84% a f t e r

r e c r y s t a l l i s a t i o n fro m a lc o h o l, mp 107-B , [ oQ q- 4 3 .7 (CHClgJ*

(1 R :2 R )-1, 2 -D im e th y l-4-c y c lo h e x e n e (1 7 ) . A m ix tu re o f N -m e th y lm o rp h o lin e

(M erck o r EGA) (1630m l) and LAH (77g) was hea ted t o 60 . C a u tio n : t h is

s t a r t in g te m p e ra tu re i s ne cessa ry because ^6 i s n o t reduced a t room

te m p e ra tu re . Then 16 (395g) was added in a few gram p o r t io n s a t a t im e a t

such a r a te t h a t th e te m p e ra tu re was k e p t <75°. Because th e m ix tu re became

v is c o u s an e f f i c i e n t s t i r r e r 16 was n e c e s s a ry . A f te r th e a d d it io n th e

m ix tu re was k e p t a t 70° f o r 1 .5 h o u r, the n hea ted t o 100 . l e f t to c o o l,

and w o rked -up by c a r e fu l a d d i t io n o f w a te r (500m l) and steam d i s t i l l a t i o n .

The upper la y e r o f th e d i s t i l l a t e was washed w i th d i lu t e HC1 and d r ie d on

sod ium . Y ie ld 8 3 .3g =84.5%, fo J ^ -1 4 3 .8 (C H C l^ ). L i t . 6 : £a lg -13B (C H C l^).

(3R:4R) - 3 , 4 -D im e th y lh e x a n e d io ic a c id ( 18 ) was p re p a re d fro m YJ_ u s in g Cope's

p ro c e d u re 23 f o r th e o x id a t io n o f b ic y c lo ^ 6 .1 .0 3 n o n e n e . The c rude p ro d u c t,

o b ta in e d in 57.3% y ie ld , was an o i l w h ich s o ld i f ie d on s ta n d in g .

(3 R :4 R )-3 , 4 -D im e th y lc y c lo p e n ta n o n e (1 9 ) . Crude ^8 was d e c a rb o x y la te d 19

w ith Ba(0H )2 to g iv e crude 1£ in 88.8% y ie ld . A f te r p u r i f i c a t i o n as th e

sem icarbazone, mp 205-8 (y e l lo w m e l t ) , £ a J^ -7 3 .4 (CHCl^) ( l i t . .

(CHC13 ) ) 19_ had [ a ] D-2 4 1 0 (CHC13 ) ( l i t . 9 : [ o ] D-1 6 0 ° (C H C lg )), g - fa c to r

0 .1 52 (c y c lo h e x a n e ). The CD o f 1£ i s d is p la y e d in f i g . 5 -4 to g e th e r w ith

th e a b s o rp tio n c u rv e .

in cyclohexane

320 nm

64

(1R:2R)- 1 ,2 -D im e thv lcvc lopen tana C20) was p rep a re d by r e d u c t io n 21 o f th esem icarbazone o f 19 i n 50% y i e l d , [a] D= [a] 5Qg-5 1 . 5 ° , [a] - 5 3 .6 ° ,

546~61 *^°* CaJ 436- 102-7Oi [ a ] 365-1 5 8 .0 ° (CHClg).Attempted r e s o lu t io n o f r a c . 19 . Rac. 19_, p rep a re d from r a c . 14 in th e same

manner as (3R:4R)-19, was t r e a t e d with "m en thydraz ide" 10 under c o n d i t io n s

as used f o r t h e p r e p a r a t io n o f th e a - io n o n e d e r i v a t i v e 2*1. The s o lu t io n was

ev a p o ra te d t o d ryness and th e r e s id u e r e c r y s t a l l i s e d from h ep tane . N e i th e r

mp nor ang le o f r o t a t i o n changed on f u r t h e r r e c r y s t a l l i s a t i o n . R egenera tiono f th e d e r i v a t i v e , mp 1 2 4 .5 -6 .0 ° . [o ]D-6 3 .0 ° (MeOH), a f t e r th e 3rd

r e c r y s t a l l i s a t i o n then gave th e Ketone, sm a ll neg. Cotton e f f e c t around

290nm, g - f a c t o r 0 .0097 (cy c lo h ex a n e ) , i . e . o p t i c a l p u r i t y 6.4%. The semi­carbazone o f t h i s Ketone gave o p t i c a l l y impure 2£, [a] -3 .7 7 ° (CHC1 ) , onr e d u c t io n 21.

I s o m e r is a t io n du r in g th e W o l f f - r e d u c t lo n . As a l r e a d y mentionned Wolff-

r e d u c t io n o f th e sem icarbazone o f 2 ,3 -d im e th y lc y c lo p en ta n o n e y ie ld e d a

m ix tu re o f ( - ) - and m eso -d im ethy lcyc lopen tane . We found i t worth w h ile to

i n v e s t i g a t e w hether th e observed c i s - t r a n s r a t i o was due to c a r e l e s s

p u r i f i c a t i o n o f th e sem icarbazone, o r to e p im e r i s a t io n d u r in g th e r e d u c t io n ,o r b o th .

E p im e r i s a t io n du r in g W olff -K ishner r e d u c t io n s has been f r e q u e n t ly

observed , bu t i n th o se cases a hydrazone was decomposed w ith o u t

in te r m e d ia te p u r i f i c a t i o n , so i t was not been e s t a b l i s h e d w hether

e p im e r i s a t io n occured d u r in g th e p r e p a r a t io n o f th e hydrazone, o r du r ingi t s decom posi t ion .

E p im e r is a t io n c l e a r l y i s a l i m i t a t i o n o f th e W o l f f - r e d u c t io n , f o r we foundt h a t m enthone-semicarbazone (21 ) , which i s e a s i l y o b ta in e d f r e e from i t s

epimer isom enthonB-semicarbazone (24 )2^ , gave a 1:1 m ix tu re o f c i s - and

t r a n s - p . -m e n th a n e ( f i g . 5 - 5 ) on r e d u c t io n 21 . A f t e r t h i s experim ent i t was

pig. s-5CH0H

25 26 27 28 29

no t s u r p r i s i n g t h a t th e sem icarbazone o f r a c . 2 ,3 -d im e th y lc y c lo p en ta n o n egave on r e d u c t io n 21 th e same c i s - t r a n s r a t i o as was found when worKing w itht h e co rresp o n d in g o p t i c a l l y a c t i v e compound.

Rac. 2 ,3 -d im e th y lc y c lo p en ta n o n e was p rep a re d acco rd in g t o f i g . 5-6 27 ) .

65

F ig . 5"6NNCNH2

HT NN CNH2^ H

21 22 23

N e n th o n e -s e m ic a rb a z o n e (2 1 3 . M en th o n e , p re p a re d by o x id a t io n 20 o f ^

( - ) - m e n th o l (F lu k a ) was c o n v e r te d i n t o i t s s e m ic a rb a z o n e , mp 1 6 6 -9 a f t e r

r e c r y s t a l l i s a t i o n (2 x ) f ro m a lc o h o l . R e d u c t io n 21 th e n gave an 1 :1 m ix tu r e

o f 22^ and 2 3 .2 . 3- D im e th v lc v c lo h e x a n o n e (2 5 3 . C h ro m ic a c id o x id a t io n 29 o f 2 ,3 - d im e t h y l -

c y c lo h e x a n o l ( A ld r ic h ) gave 25 i n 94% y i e l d .

2 . 3 - D lm e th y l - 6 -h y d ro x v m e th y le n e -c y c lo h e x a n o n e (26_). A p ro c e d u re f o r th e

p r e p a r a t io n o f h y d ro x y m e th y le n B -c y c lo h e x a n o n e 30 was used t o g iv e 26 in

70.7% y i e l d .2 . 3 - D lm e th y lh e x a n e d io ic a c id ( 2 7 ) 2 7 . B ecause 1 can be o z o n is e d t o g iv e 6

i n h ig h y i e l d 2 0 , i t was w o r th w h i le t r y i n g t o p re p a re 27 fro m 26 i n th e

same m anne r. 26 (5 5 .0 g ) d is s o lv e d i n CC14 and c o o le d i n ic e was o z o n is e d .

To th e s o lu t io n o f th e o z o n id e w a te r (3 0 0 m l) was a d d ed , and w h i le

v ig o r o u s ly s t i r r i n g th e CC14 was d i s t i l l e d o f f . The aqueous s o lu t i o n , made

a lk a l i n e , was e x t r a c te d w i t h e t h e r , th e n made a c id , and 27 was is o la t e d by

e t h e r e x t r a c t io n . From 26^ ( 1 5 9 .9g ) was o b ta in e d i n t h i s m anner c ru d e 27

(1 4 9 g = 0 2 .4 % ): an o ra n g e - re d o i l .

2 . 3- D im e th y lc v c lo p e n ta n o n e ( 2 0 ) . C rude 27 (1 4 9 g ) was d e c a rb o x y la te d 19 w i t h

B a (0 H )_ t o g iv e p u re 2J3 ( 6 2 .Og =64.6% ) a f t e r d i s t i l l a t i o n .

1 .2 -O im e th y lc v c lo p s n ta n e ( 2 9 ) . 28 was c o n v e r te d i n t o i t s s e m ic a rb a z o n e .

P a r t o f th e c ru d e s e m ic a rb a z o n e was k e p t , th e re m a in d e r was r e c r y s t a l l i s e d

(3 x ) f ro m n . b u ta n o l . The p u r i f i e d s e m ic a rb a z o n e had mp 2 1 0 .0 - 4 .5 ° (d ) on

r a p id h e a t in g . R e d u c t io n 21 o f b o th c ru d e and p u r i f i e d s e m ic a rb a z o n e gave a

m ix tu r e o f c is -2 9 ^ (16 .5 % ) and t r a n s - 2 9 (0 3 .5 % ).

One o f th e a u th o rs (Kokke) i s in d e b te d t o th e N e th e r la n d s O rg a n iz a tio n f o r

th e Advancement o f Pure Research (Z .W .0 .) f o r th e s p o n s o r in g o f t h i s w o rk .

A NATO g ra n t f o r th e pu rchase o f q u in id in e i s g r a t e f u l l y acknow ledged.

The a u th o rs owe t h e i r g r a t i tu d e t o P r o f . L .J . O o s te rh o f f who proposed to do

th e work re p o r te d in t h i s p a p e r, and t o P r o f . H. Wynberg (G ron ingen) f o r

Acknow ledgem ent.

r e a d in g and com m en ting th e m a n u s c r ip t .

66

R e fe rences .

3) E .D . E n g B lh a rd t, K o n in K li jK e /S h e ll E x p lo ra t io n 8 P ro d u c t io n L a b .,

R i js w i jk ( Z .H . ) , The N e th e r la n d s , to be p u b lis h e d .

2 ) R. Deen, u n p u b lis h e d r e s u l t s .

3) R .K. H i l l , P .J . F o le y and L .A . G a rd e lla , J . O rg. Chem., 32, 2330 (1 9 6 7 ).

**) The a b s o lu te c o n f ig u r a t io n o f th e compounds in t h i s pa pe r fo l lo w fro m

th e work in 3) and 5 ) .

5 ) H.M. W a lb o rs k i, L. Barash and T .C . D a v is , T e tra h e d ro n , 19, 2333 (1 9 6 3 ).

6 ) F o r a p ro o f o f th e s t r u c tu r e o f t h i s c o n d e n s a tio n p ro d u c t see:

L. T é t r y , B u l l . Soc. Chim. F r . , { 3 } 27 , 302 (1 9 0 2 ).

' ) We bo rrow ed th e id e a to use N -m e th y lm o rp h o lin e from

R.R. Sauers and J .A . W i t t l e , J . O rg. Chem., 34, 3579 (1 9 6 9 ).

° ) F o r re p re s e n ta t iv e y ie ld s in LAH re d u c t io n s o f su lphonatB S in THF o r

e th e r t o g iv e s im p le h y d ro c a rb o n s , c f . 5 ) and J .F . B u s s e r t ,

K.W. G reen le e , J .M . D e r fe r and C.Ë. B oord , J . Amer. Chem. S o c .,

76, 6076 (1 9 5 6 ).

9 ) B. Cammalm, A c ta Chem. S can d ., 10, 477 (1 9 5 6 ). ■

1®) R.B. Woodward, T .P . Kohman and G.C. H a r r is , J . Amer. Chem. S o c .,

63 , 120 (1 9 4 1 ).

* * ) E. G ild e m e is te r and F r . H offm ann, D ie E th e r is c h e n O e le , 4 . A u f l . ,

A kad em ie -V e rlag , B e r l in , Bd I I I c , 228 (1 9 6 3 ).

12) H. Rupe, A n n ., 436, 202 (1 9 2 4 ).

13) 0 . W a lla c h , B e r . , 29 , 1596 (1 8 9 6 ).

1‘t ) R. Poggi and P. S a l t i n i , Gaz. Chim. I t . . 62 , 680 (1 9 3 2 ).

33) W.S. Johnson, J . Amer. Chem. S o c ., 65 , 1320 (1 9 4 3 ).

18) A v ib ro -m ix s t i r r e r was used (A .G . f u r C hem ie -A ppara tebau , Z u r ic h ,

S w itz e r la n d ) .

^ ) F.G. G a u lt , J .E . Germain and J .-M . C on ia , B u l l . Soc. Chim. F r . ,

1064 (1 9 5 7 ).

18) W.S. Johnson, J . Amer. Chem. S o c ., 66 , 216 (1 9 4 4 ).

19) O rg. S y n th ,. C o l l . V o l. 1 , 192.

2®) H. N e reshe im er, D is s e r ta t io n K ie l (1 9 0 7 ).

2 * ) K .W .F. K o h lra u s c h , A.W. R e iz and W. S to c k m a ir , Z . P h y s ik . Chem.

( L e ip z ig ) . B 32. 234 (1 9 3 6 ).

2 2 ) G. A b a t i and C. De H o r a t i is , Gaz. Chim. I t . , 39 , 553 (1 9 0 8 ).

2 3 ) A.C . Cope, Sung Moon and Chung Ho P a rk , J . Amer. Chem. S o c .,

84, 4843 (1 9 6 2 ).

67

21t) Y.-R. Naves, Helv. Chim. Acta, 30, 769 (1947).25) C. Djerassi, T.T. Grosnickle and L.B. High, J. Amer. Chem. Sac.,

78. 3166 (1950).W.S. Johnson, A. van der Gen and J.J. Swoboda, J. Amer. Chem. Soc.,

69. 170 (1967).W.S. Johnson, G.A. Harbert and R.D. Stipanovic, J. Amer. Chem. Soc.,

90_, 5279 (1968).N.S. Crossley and H.B. Henbest, J. Chem. Soc., (1960) 4313.R.K. Hill, J.G. Martin and W.H. Stouch, J. Amer. Chem. Soc.,

83, 4006 (1961).

2® ) M. Delépine and M. Badoche, Compt. Rend., 228, 19 (1949).M. Badoche, Ann. Chim., {12} 4_, 449 (1949) j Ind. Parf., 10.,

180, 238 (1955).27) A plan for the preparation of 27_ by selenium dioxide oxidation of 25

followed by H20_-oxidation of the diketone obtained (fig. 5-7) was

■C00H-C00H

rejected because cyclohexanedione can be prepared from cyclohexanoneonly in low yield based on ketone: 10.4% (Org. Synth., 32, 35 (1952)),19.6% (A.I. Vogel, Practical Organic Chemistry, 3rd ed., 975).

2®) E. Beckmann, Ann., 250 322 (1888).2^) A. Killen Macbeth and J.A. Mills, J. Chem. Soc., 709 (1945).30) Org. Synth., Coll. Vol. 4, 536.

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68

CHAPTER S IX

TWO METHODS FDR THE DETERMINATION OF OPTICAL PURITY.

DETERMINATION OF OPTICAL PURITY USING CIRCULAR POLARIZATION OF

LUMINESCENSE.

S i r :

The method o f c i r c u la r p o la r iz a t io n o f lum inescensB (C P U , w h ich has

been deve loped by Emeis and O o s te rh o f f1 2 , has many p o t e n t ia l

a p p l ic a t io n s 1 3 L One o f them , th e d e te rm in a t io n o f o p t ic a l p u r i t y , has

been proposed by E a ton5 . The suggested p ro c e d u re 5 re q u ire s th e measurement

o f CPL o f th e m ix tu re o f en a n tio m e rs o f Which th e o p t ic a l p u r i t y has to be

d e te rm in e d and o f a race m ic m ix tu re . However, a race m ic m ix tu re may n o t

always be a t hand, e .g . i f th e m ix tu re o f en a n tio m e rs has re s u lte d from th e

c o n v e rs io n o f a n a tu r a l p ro d u c t. M oreove r, th e e f f e c t in CPL o f a racem ate

m ig h t be to o s m a ll f o r measurement because i t i s a f a c t o r ig s m a lle r tha n

th e e f f e c t o f an o p t ic a l l y pu re compound5 .

I t w i l l be shown th a t th e use o f a racem ate can be a vo id e d .

L e t us c o n s id e r a homogeneous m ix tu re o f e n a n tio m e rs , L and R,

c o n ta in in g n^ m o lecu les o f L and n „ m o lecu les o f R. A q u a n t i ty p r e la te d t o

th e o p t ic a l p u r i t y (= 100 |p I (%)) i s th e n d e f in e d as

V nRnL+nR

-'UpS+1 ( 1 )

I r r a d ia t io n o f t h i s m ix tu re w ith l e f t c i r c u la r l y p o la r iz e d (1 ) l i g h t

g iv e s r is e t o e x c ite d s ta te p o p u la t io n s o f L and R, n * and n * ,

n! S nL 1 nR=a2 nRwhereas i r r a d ia t i o n w ith r ig h t c i r c u la r l y p o la r iz e d ( r ) l i g h t o f th e

same w a ve le ng h t and in t e n s i t y r e s u l t s in

nL=a2nL * nR=ai nR •

The c o e f f i c ie n t a^ i s p r o p o r t io n a l t o th e in t e n s i t y o f th e e x c i t in g

l i g h t , and to th e m o la r e x t in c t io n c o e f f i c ie n t e , p e r ta in in g

to m o le cu le s o f L a b o rb in g 1 - l i g h t o r to m o le cu le s o f

R a b s o rb in g r - l i g h t 6 .

I t i s c o n v e n ie n t to in tro d u c e a q u a n t i ty X as

X - • V a2V a2

er e2e +e1 2

The intensities of 1-light and r-light, 1^ and Ir , in theluminescense excited by 1-light depend on the excited statepopulations according to

I * s(en* + (1-e)n*) ;1 L * R*I = std-eln^ + enR).

We define e as the fraction of the intensity of the light emittedby L which is 1-light at the wavelenght of observations s is aproportionality constant.

It is useful to introduce

Il~Ir _ a1nL~a2nR _ „ P+XXl= Ïj+Ij. " «1nL+02rtR 1+PX '

where Y is defined as

Y“ 2e"1 = ^lum 'and the index 1 of x indicates that the mixture has been irradiated

with 1-light. Similarly one finds

v »Y E ' ~ -.xr 1-pXNumerical values for xx and xr follow from CPL measurements.

The third equation to determine the optical purity t = 1001p13is obtained by measuring the CD and absorption of thB mixture.We define $ as the half of the ratio of the effects in CD and

in absorption.

where e is the extinction coefficient of the mixture of L and Rfor 1-light. To derive that $=pX use has been made of formula (10)and the analogue expression for er.

nL nRV nL+nR e1 + nL+nR e2

Then p can be calculated using the formula

2 X1*Xr*»(x1-Xr)P = 9 X^X/GCx^Xj.)

which follows from (6), (B) and (9).When p is determined then the numerical values of g=2*/|p| and

a =2Y which characterize the optical activity of a molecule inBlum . , . .its ground state and in its excited state can be found bystraightforward calculations .

(6)

(7)

(B)

(9)

(10)

(1 1)

70

ACKNOWLEDGEMENT: The author Is indebted to Prof. L.J. Oosterhoff for hishelp in improving the presentation of this paper. This work has beensponsored by the Netherlands Organization for the Advancement of PureResearch (Z.W.O.).

References.1) C.A. Emeis and L.J. Oosterhoff, Chem. Phys. Letters, 1_, 129 (1957).2) C.A. Emeis, Thesis Leiden (1968).3) H.P.J.M. Dekkers, C.A. Emeis and L.J. Oosterhoff, J. Amer. Chem. Soc.,

91, 4589 (1969).**) A. Gafni and I.Z. Steinberg, Photochem. Photobiol., 15, 93 (1972).5) S.S. Eaton, Chem. Phys. Letters, 8, 251 (1971).6) Note: (2) and (3) only hold if Lambert-Beer’s law is valid.7) For the evaluation of Y from (6) or (8) and (9) the sign of p,

calculated from (11), is chosen in such a way that Y gets the same signas (Xj+XjJ-

W.C.M.C. KokkeDepartment of Theoretical Organic Chemistry,University of Leiden,P.0. Box 75, Leiden, The Netherlands.

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71

PHOTOCHEMICAL DETERMINATION OF OPTICAL PURITY.

Sir:When an aqueous solution of optically active potassium trisoxalato

chromate-(III) Is irradiated, interconversion of the two antipodes, whichwith unpolarized light leads to racemisation, takes place. Stevenson8,using circularly polarized light, showed that partial photoresolution ofthis compound and of several other complexes could be realized. He derivedthat the ultimate attainable optical purity in such a reaction could be|igCX)I-100% if the assumption that there are no absorbing intermediatesholds. Although this maximum attainable optical purity is rather low, inthe case of potassium trisoxalato chromate-(III) it was enough to permitCD measurement from which the effect in CD of the optically pure complexcould be calculated.

We suggest an extention of Stevenson's idea to the photochemicaldetermination of optical purity of organic compounds. The method consistsin calculating thB optical purity of a suitable organic compound from thetime dependence of its effect in CD on irradiation with right circularlypolarized (r) light and with left circularly polarized (1) light. Themethod is applicable only to compounds which on irradiation give rise tophotoproducts that do not absorb the exciting light2.

Let us consider a homogeneous mixture of enantiomers, L and R,containing n^ molecules of L and n^ molecules of R. A quantity p relatedto the optical purity (=100|p| (%)) is then defined as

V nRnL+nR

Irradiation of this mixture with 1-light gives rise to excitedstate populations of L and R, n. and n^ ,

nL=ainL * nR“a2nR *s n„=a,,nwhereas irradiation with ■light of the same wavelength andintensity results in

nL’a2nL nR=alnRThe coefficient a. is proportional to the intensity of the excitnglight, and to the molar extinction coefficient pertainingto molecules of L absorbing 1-light or to molecules of

(1 )

(2)

(3)

R absorbing r-light1

72

In the 'Following it is assumed that the compound decomposesunimolecularly on irradiation with unpolarized light.

We define R to be the antipode having a positive effect in CDat the wavelength of irradiation. Then because a2>a,j L will decomposefaster than R when the mixture is irradiated with r-light:

nLtt)’nL(0)exp("aa2tJ 1 nR(t}=nR (°)exp(-aa,]t} (43where

oia^BCe-l |Ae|3 and a2»B(e+J |Ae|) (5)are rate constants which depend on the intensity of the excitinglight and on the quantum yield of the photo reaction.

It is useful to introduce a quantity XC13 as the ratio ofthe effects in CD during and at the beginning of the irradiationexperiment.

n. (t)-n (t)YM-1 = — =____ n

J nL(0)-nR (0)Substitution of (43 in (63. using (53 gives

X (t)=exp(-Bet)nLC0)exp(-J3t|Ae|)-nR (0)exp(J3t|Ae|3

n^(0)-nR (0)where the index r of X indicates that the expression refersirradiation with r-light.

This expression can be simplified when exp(-JBt|Ae|3 andexp(J3tIAe|3 are expanded in a Taylor series!'

X p t t j + e x p c - e e t ) [1+ j e t $ / p 2 + j ( j e t $ / P ) 2 + . . . . . jwhere $=|p|Ae is the effect in CD of the mixture of enantiomersat t=0 at the wavelength of irradiation.

Numerical evaluation of the terms in between brackets in (032shows that J(j0t*/p) is small compared with the other two termsand in most cases can be neglected.

The expression, similar to (83, for irradiation with 1-light isX ^ t J - e x p C - B e t ) [1- J e t $ / p 2 ] .

Numerical values of 3 follow from the sum of (83 and (93:ln(JX_(t)+JX (t))»-3et 11 12).

Then p follows fromX.(t)-X (t3_1____ r -Bt$X.(t)+X (t3 „ 2 *1 r 2p

ACKNOWLEDGEMENT: The author is indebted to Prof. L.J. Oosterhofffor his interest in this work.

(63

(73

(8)

(9)

(10)

(11)

73

References.8) K.L. Stevenson, Thesis University of Chicago [1968), Univ. Microfilms,

Ann Arbor (Mich.), order number 69-1245.K.L. Stevenson and L. Verdieck, J« Amer. Chem. Soc. , 90, 2974 (1968).

9) The method might be applied to a-diketones, cf.B.M. Monroe, Adv. Photochem., vol. 8, 77 (1971).

10) The derivation holds only if the Labert-Beer law is valid.11) xn principle the decay, due to excitation with 1- and r-light, of the

optically impure compound can be followed in absorption as well, butthese decay curves X(t)=(n (t)+np(t))/(n^(0)+n^(0)) are less sensitiveto the value of p than the decay curves obtained from CD measurements.F.e. one derives:Sfr(t)=exp(-3et) [l+ Bt$+ J($3t4>/p)2+ ..... ] »so that p only occurs in thB third term which in most casesis neglegible.

12) In principle both 3 and $ can be derived from only one decay curvebut the proposed method is much more accurate.

W.C.M.C. KokkeDepartment of Theoretical Organic ChemistryUniversity of Leiden, P.0. Box 75,LeidBn, The Netherlands.

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74

APPENDIX1R 1 ftINCOMPLETED WORK ON 0- O-DIKETONES AND SUGGESTIONS FOR FURTHER WORK

General.16 16The stages in the synthesis of an 0- O-diketone are:

1/ The preparation of a compound of known absolute configuration and18optical purity, suited to Introduce the °0-label.

182/ Introduction of the label. This 0-label must be high because the18effect in optical activity due to O-substitution will always be very

small compared with the Bffect in optical activity of e.g. a C -ketone.3/ The conversion of the labeled compound into the desired diketone.Much work in stage 1 can be saved if a natural product can be chosen as astarting material, because then work for the resolution and determinationof optical purity can be avoided.It is economically attractive trying to combine stage 2 and 3, thus making

18the introduction of 0 the last step in the synthesis.

The possibilities for the introduction of isotopes of oxygen areexchange, hydrolysis and oxidation1.- Labeling of a carbonyl compound isgenerally carried out by heating amixture of the compound with water,

18enriched in 0, if necessary withsome solvent, and a catalyst2,although even without a catalystexchange can be effected3. Anotherpossibility for labeling by exchange

18is irradiation of a mixture of 0^and ketone at about 300nm . But thenpartial photolysis cannot be avoided.

16Labeling by exchange is the most expensive manner (based on costs of °0]18for the introduction of an 0-label, because for the introduction of a

18label of. e.g. 60% 0, an Bxcess of expensive, more highly labeled water isnecessary (cf. table). In principle it is possible to recover labeled waterafter such an exchange reaction, but its label will be too low to permit

16 18its usage for the synthesis of another 0- O-diketone. Thus foreconomical reasons the possibility of labeling by exchange can only be

OXYGEN-18 ENRICHED WATER*18unnormalized (0 °0)

isotopic standard packagesenrichment size pri ce(atom %) (max.)

1.5 200g $ 703 50g $ 13510 15g $ 30020 5g $ 22540 3g $ 32060 2g $ 40080 1g $ 32090 1g $ 36097 1g $ 400

X) Miles Laboratories Iric.

75

considered if other attempts for the introduction of a label have failed.- For the labeling of a ketone by hydrolysis of a functional derivative,every functional derivative which does not contain oxygen and can behydrolysed easily is suitable, such as hydrazone, enamine, N-isopropyl-imine and thioketone. In addition functional derivatives such as acetaleor enol-ether can be used, because under normal conditions of hydrolysisof these compounds, the alcohol formed cannot exchange oxygen with labeledwater.Sometimes it will be convenient to select a crystalline derivative of theketone for labeling because then purification of the ketone and labelingcan be done in one step.- The only practical method for the preparation of an highly labeled180-ketone by oxidation, is the photo-oxidation of a thioketone with 02-

A discussion of the particular projects.It is considered useful to describe in this appendix incompleted work

and to add suggestions for futher syntheses, because together with thework in chapter 2 this might give a clear picture of experimentaldifficulties to be encountered in this kind of isotopic synthesis.

Fig, 7-1 gives the structural formulae of the diketonBS discussed inthis appendix. These compounds belong (at least time-averaged) to the pointerouos C , C or C, before introduction of the isotope and are chosen“ s 2h i

subject to the condition that they should be as small as possible andpreferentially rigid, otherwise it will be far too difficult, if notimpossible to analyse the CD spectra of their optically active D- 0-analogues. Open chain diketones are not interesting because of the manyconformations in which they may exist.

We have devoted our experimental attention to the first three compounds(fig. 7-1) only. Referring to the other projects suggestions are given

76

w h ich m ig h t be u s e fu l i f a s y n th e s is o f such an 160 - 1S0 -d ik e to n e f o r th e

s tu d y o f i t s o p t ic a l a c t i v i t y i s s ta r te d .

2 ,6 -D ike to -cam ph an e (7 )

I t i s p ro b a b ly p o s s ib le to p re p a re s p e c i f i c a l l y la b e le d 160 - 2 ,6 - d ik e to -

camphane ( .7) f o l lo w in g th e c la s s ic a l s y n th e s is o f t h i s compound5 ( f i g . 7 -2 ) .

I ^ j # 0 H?NCH ^ -y *N0H H;SO< ^ _JN 1 KMnO< O H ^ O O H H* ° ^ j j C° w °

F ig u re 7 -2

One m ig h t in tro d u c e th e la b e l in a -c a m p h o lo n ic a c id (6 ) by exchange w ith

w a te r , e n r ic h e d in □. S e le c t iv e la b e l in g o f th e c a rb o n y l group in 6 is

p o s s ib le because a c a rb o n y l g roup exchanges oxygen f a s t e r tha n th e

c a rb o x y l g roup o f a weak a c id ( c f . th e la b e l in g o f b u t y r ic a c id 5 ) .

As a lre a d y e x p la in e d la b e l in g by exchange i s e x p e n s iv e , and to save18

money a s y n th e t ic a l ro u te to Q -^ , n o t in v o lv in g la b e l in g by exchange,

had to be deve loped ( f i g . 7 - 3 ) . I t was known th a t in th e o x id a t io n o f

,OAc ,Cr„0

F ig u re 7 -3 HOAc(ACÏ2O

b o rn y la c e ta te (EH w ith ch ro m ic a n h y d r id e in a c e t ic a c id / a c e t ic a n h y d r id e ,

e xce p t f o r 6 -a c e to x y -e p ic a m p h o r, 6 -a ce to xy -ca m p h o r (9 ) was a ls o fo rm e d 7 ,

a lth o u g h had n e ve r been is o la te d . We succeeded in s e p a ra t in g 9 and

6 -a c e to x y -e p ic a m p h o r by d i s t i l l a t i o n , b u t p re p a ra t io n o f 9 o r 11 w ith th e

c a rb o n y l g roup la b e le d w i th 0 (by h y d r o ly s is o f a f u n t io n a l d e r iv a t iv e

o r ph o to o x id a t io n o f a th lo k e to n e ) was n o t p o s s ib le , 'because s u i ta b le

d e r iv a t iv e s o f £ c o u ld n o t be o b ta in e d .

Thus th e ways l e f t were e i t h e r to la b e l 6 , 9 o r by exchange8 , o r to f in da n o th e r ro u te to 7.

The new ro u te proposed i s a v a r ia t io n o f th e c la s s ic a l s y n th e s is o f 7

( f i g . 7 - 4 ) . None o f th e s te p s in t h i s s y n th e s is w i l l p re s e n t, in p r in c ip le ,

any in s u rm o u n ta b le d i f f i c u l t y , e xce p t f o r th e p re p a ra t io n o f 6 -m e th y le n e -

camphor M £ ) by th e rm a l r in g c lo s u re o f th e a c e ty le n ic ke tone 15. C o n ia9

77

^ j b h . 9 -B B N

3 4 12

CHzBr

NaC=CH

xx <V K s * CH* A (?) 0 ^ | C=CH jw e s o x OH C=CH

F ig u re 7 -4

has d e s c r ib e d th e p re p a ra t io n o f f l-m e th y le n e -b ic y c lo [ 3 . 3 . lJ n o n a n e -2 -o n e by

such s r in g c lo s u re , b u t i t i s n o t known w h e th e r t h i s r in g c lo s u rs re s c t io n

is a p p l ic a b le to th e p re p a ra t io n o f s m a lle r r in g system s such as 16^

T ra n s -b ic y c lo [*3 .3 .cT[ o c ta n e - 3 , 7~d ione C2 3 )

Because 5 -h y d r in d e n e -2 -o n e (22 ) ( "h y d r in d e n o n e ” ) had been p re p a re d in

th e D epartm ent o f T h e o re t ic a l O rg a n ic C h e m is try in L e id e n 10 b e fo re in te r e s t

had r is e n in ^ 0 - compounds, i t was an ob v io u s e x te n s io n o f t h i s e a r l ie r

w ork to a tte m p t p re p a ra t io n o f t r a n s - b ic y c lo £ 3 .3 .o ]o c ta n e - 3 ,7 - d io n e (£3)

fro m 22 ( f i g . 7 - 5 ) . A f te r methods f o r r in g open ing in 22 o r in

Cf>»—°=cf>°^COOH U i

3 STEPS

%/OTs

F ig u re 7 -5

h y d r in d e n y la c e ta te (24 , f i g . 7 -7 ) had f a i l e d o r were found u n s a t is fa c to r y ,

s y n th e s is o f 23 fro m 22 was a tte m p te d v ia r in g c o n t ra c t io n .

R'rr '

p ' ^ B r

R \ ^ °

R- ^ 0V"A , ‘COOH

F ig u re 7-6

We based o u r approach ( f i g . 7 -7 ) on an id e a o f W a lla c h 11 f o r r in g

c o n t ra c t io n o f c y c lo a lk a n o n e s ( f i g . 7 -6 ) a f t e r we had v e r i f i e d t h a t le ad

d io x id e o x id a t io n o f o i-h y d ro x y -c y c lo p e n ta n e -c a rb o x y l i e a c id g iv e s a h ig h

y ie ld o f c y c lo p e n ta n o n e , and because a h ig h y ie ld i s re p o r te d in th e

b e n z i l l i c a c id rea rran gem e n t o f cyc lo h e x a n e d io n e 12. The d ion e 27_ was

78

o

24 25 26 27 28

F ig u re 7 -7

p re p a re d as in d ic a te d in f i g . 7 -7 , b u t th e s y n th e s is was n o t com p le te d .

An a l t e r n a t iv e f o r th e p re p a ra t io n o f 27 i s h y d ro x y la t io n o f 24 by

OsO fo llo w e d by R u O .-o x id a t io n j an a l t e r n a t iv e f o r r in g c o n t ra c t io n by

b e n z i l l i c a c id rea rran gem e n t m ig h t be th e THNGg) ^ r e a c t io n w ith a lk e n e s 13:

fro m h y d r in d e n o l the n b ic y c lo [3 .3 .q ]o c ta n e -3 -o l-7 -c a rb o x a ld e h y d e sh o u ld be

fo rm ed , w h ic h , a f t e r c o n v e rs io n in t o th e c o rre s p o n d in g c a r b o x y l ic a c id ,

m ig h t be c o n v e rte d in t o £3 u s in g s ta n d a rd d e g ra d a tio n p ro c e d u re s .

The r e s o lu t io n o f 4 - c y c lo h e x e n e -1 ,2 -d ic a rb o x y lic a c id i s d e s c r ib e d in

c h a p te r 5 , th u s th e p re p a ra t io n o f o p t i c a l l y a c t iv e 22 p re s e n ts no

d i f f i c u l t i e s . Me have a ls o a tte m p te d th e r e s o lu t io n o f 22 w ith th e Woodward

re a g e n t1** "m e n th y d ra z id e ” , and w ith 4 - (e n d o -2 - fe n c h y l) -s e m ic a rb a z id e , b u t

o u r e f f o r t s were n o t re w a rd in g .

C 1 s :3 r :7 r ; 9 s ) - T r ic y c lo f7 .3 .0 .0 3 ‘ ’:lld o d e c a n e -5 ,1 1 -d io n e (3 5 ) .

' . t = H H

Bq (0H>2 HOOCA HOOC

-COOH KMnOj'C00H acetone

36 35

F ig u re 7 -834 33

The s y n th e s is o f _35 ( f i g . 7 -8 ) was s ta r te d a f t e r we had fo u n d in th e

l i t e r a t u r e t h a t s t e r i c a l l y pu re 33 had a lre a d y been d e s c r ib e d 13. The easy

s y n th e s is o f _33 i s based on th e happy c irc u m s ta n c e th a t th e d ik e to n e 30

has a mp abou t 90 h ig h e r th a n any o f i t s e p im e rs 13, r e s u l t in g in an easy

p u r i f i c a t i o n o f ^ 0 . The o x id a t io n o f 33 and th e subsequent d e c a rb o x y la t io n

p roceed in low y ie ld , m aking i t d i f f i c u l t to p re p a re la r g e r q u a n t i t ie s o f

35, w h ich a re necessa ry i f th e s y n th e s is o f 35 i s to be extended to th e

79

16 16s y n th e s is o f th e c o rre s p o n d in g o p t ic a l l y a c t iv e 0 - 0 -d ik e to n e .

The ess ignm ent o f s t r u c tu r e 35 and n o t 36 to th e d e c a rb o x y la t io n p ro d u c t13

o f 34 i s based on e v ide nce fro m IR and C-NMR.

3 . 5-D iketocam phane (4 0 ) .

.•O -C -SC H 3

° -

\/ 0 ^ ^ O H ^ ^ - O H O ^ - ^ OOM

39 40

1 41 42

F ig u re 7-9

The s y n th e s is o f 3 , 5-d ike to -ca m p h a n e (40 , f i g . 7 -9 ) i s a s id e p a th o f

th e s y n th e s is o f 2 ,6 -d ik e to -c a m p h a n e (_7, f i g . 7 -3 ) because a b y -p ro d u c t

o f th e l a t t e r s y n th e s is , 6 -a c e to x y -e p ic a m p h o r (1 7 ) , can be used f o r th e

p re p a ra t io n o f 4 0 .The S -m e th y l-x a n th a te 37 on th e rm o ly s is g iv e s a m ix tu re o f th e th re e

exp ec ted p ro d u c ts fro m w h ich can be is o la t e d 17. T h is de hyd ro -ep icam pho r

(38 ) i s r e a c t iv e and s ta b le enough to p e rm it la b e l in g by h y d ro ly s is o f a

f u n c t io n a l d e r iv a t iv e 18. H y d ro b o ra tio n o f and o x id a t io n w i l l produce 4£

to g e th e r w i th 2 , 5-d ik e to -c a m p h a n e . The o n ly d i f f i c u l t y w i l l be s e p a ra tio n

o f th e s e two d ik e to n e s .

The s y n th e s is o f 38 fro m b o rn y le n e (42 ) by a u to x id a t io n has been

re p o r te d by Japanese w o rk e rs 19. O p t ic a l ly pu re b o rn y le n e (42 ) i s e a s i ly

p re p a re d fro m c a m p h o r-to s y lh y d ra z o n e 20 (4 1 ) , b u t i t i s n o t known w h e the r

38 can be p re p a re d fro m 42 w ith r e te n t io n o f o p t ic a l a c t i v i t y .

V5

B ic y c lo f 3 . 3. l1 n o n a n e -2 ,8 -d io n e (4 5 ) .

As a lre a d y m en tionned in c o n n e c tio n w i th a p lanned s y n th e s is o f

2 , 6-d ike to -ca m p h a n e f i g . 7 -4 )

th e a c e ty le n ic ke tone ^ ( f i g . 7 -1 0 )9ondergoss r in g c lo s u re on h e a t in g

to g iv e 8 -m e th y le n e -b ic y c lo [3 .3 .1 ^ ]-

nonane-2 -one ( 4 ^ ) . I f 44 can be

re s o lv e d and la b e le d , th e n p re p a ra t io n

0/ /

44

F ig u re 7-10

80

/J 0 «10o f o p t i c a l l y a c t iv e 0 - 0-4J5 w i l l p ro b a b ly p re s e n t no d i f f i c u l t i e s .

5 , 5 - D im e th y 1 - b ic y c lo \2 . 1 . £ | h e x a n e -2 ,3 -d io n e (4 9 ) .

cn2 oF1'“” 7' ” (£) (£) — < E f ■

46 47 46 49

M e in w a ld 21 p re p a re d 5 , 5 - d im e t h y l - b i c y c lo | ^ . 1 . lJ h e x a n e -2 -o n e (4 8 , f i g .

7 -1 1 ) f ro m n o p in o n e (4 7 ) by r i n g c o n t r a c t io n . The c o r re s p o n d in g d ik e to n e

49 i s s t i l l unknow n. The b e s t s t a r t i n g m a t e r ia l f o r a t te m p t in g th e

p r e p a r a t io n o f a b i c y c l o \2 . 1 . lJ h e x a n e - 2 ,3 -d io n e i s th e u n m e th y la te d

a n a lo g u e o f 4 8 , because t h i s m o n o -k e to n e i s a v a i la b le by p h o t o - c y c l i s a t io n

o f v in y l - ( 2 - p r o p e n y l ) - k e t o n e 2 2 .

7 , 7 - D lm e t h y l - b lc y c lo p ) . 1 . l1 - 3 - o c te n e - 2 ,5 - d io n e ( 5 4 ) .

F ig u r e 7 -1 2\

COOH

50 51 52 53 54

I t i s i n t e r e s t i n g t o know w h e th e r p in o n a ld e h y d e 2 ^ (5 2 ) can u n d e rg o an

in t r a - m o le c u la r a ld o l c o n d e n s a t io n t o g iv e th e u n s a tu ra te d k e tp n e 53.

U s in g some re a g e n t f o r a l l y l i c o x id a t io n i t w i l l th e n c e r a in ly be p o s s ib le

t o c o n v e r t 53 i n t o 5 4 ; even a u t o x id a t io n can p o s s ib ly be used t o p ro d u c e

5 4 , because 3 -c a re n e (5 5 )

F ig u r e 7 -1 3 / - q; can be a u to x id iz e d t o g iv e a

com pound21* ( 5 6 ) ( i n a p o o r

y i e l d ) w i t h a s i m i l a r3 0 3 0 3 7

ch ro m o p h o re as ^ 4 . F o rm a t io n

o f jtö f ro m c a re n o n e (5 7 ) has n o t been r e p o r te d .

3 , 3 - O im e t h y l - b ic y c lo T 3 .1 . 0*1 h e x a n e -2 ,4 -d io n e ( 6 0 ) .

58 59

F ig u re 7 -1 4

C y c lo p e n te n e -3 ,5 -d io n e (_58) i s e a s i l y

o b ta in e d ( i n tw o s te p s ) fro m c y c lo p e n te n e 2 ®;

i t w i l l be p o s s ib le t o p re p a re th e

c o r re s p o n d in g 4 ,4 -d im e th y l-c o m p o u n d (5 9 ) fro m

d im e th y l- c y c lo p e n te n e , b u t p r e p a r a t io n o f 59

81

by methylation of 56 or a dsrivativs will bs difficult if possibls at all26). A best chance for the closure of the three membered ring is to use theCorey reagent dimethyl-oxo-sulphonium-methylide27, which is Known to reactwith activated double bonds in a-unsaturated Ketones. However, no exampleis Known of a reaction of this reagent with a 2-butene-1,4-dione chromo-

phore.

Compounds with a tricyclo f5.1 ■ 0.03'51 octane-2,6-dione structure.Little experimental attention has beenpaid to compounds with the tricyclo-[5.1.0.03’ 5J octane-2,6-dione structure(61, 62). Both 61_ and its cis-analoguehave been reported3®, and also the cis-analogue of £1 with all of its bridge­heads methylated29. Little is Known about

the stability and reactivity of these compounds. But this Knowledge will be

Figure 7-15

essential in order to judge the feasibility of a synthesis of opticallyactive 160-1S0-61 or -62. It might be found advantageous to synthesize160-180-61 not from trans-61, but from ^O-^O-bicyclo^.I.O^-S-heptene-2,5-dione (63). In that case 3,7,7-trimethyl-61 (=66) which can be preparedfrom canzone30 (64) (cf. fig. 7-16) might be used as a model compound.

OH 0

C2H5OHFigure 7-16

Experimental.Melting and boiling points are not corrected. Angles of rotation weremeasured with a Bendix-NPL photoelectric polarimeter, or with a PerKin-Elmer polarimeter (model 131) at room temperature» mass spectra wereobtained with a MS-9 mass spectrometer.

Experiments concerning section "general".Thlocamphor, stability in the absence of light and oxygen. We found thatphoto-oxidation of a thioKetone could be a convenient labeling procedurebecause in a reference31 in a review on thioKetones32 was stated that

82

thiocamphor is not stable, whereas we had Kept a sample of thiocamphor ina refrigerator for over a year without any detectable chemical change-. Itwas found that irradiation of carefully degassed solutions of thiocamphorin CC14, benzene, CHC13 and iso-octane (optical density -vl.5 (1cm cell)) inthe absorption band in the visible region caused no change in theabsorption spectrum. Even after storage of these solutions for over threeyears the absorption spectra had not changed at all. But irradiation ofsolutions of thiocamphor in the presence of oxygen gave camphor as the mostimportant reaction product. A similar photo-oxidation reaction of thio-benzophenone has already been described in the literature33.Thiocamphor, preparation32. If a small quantity of thiocamphor is desired,this is most conveniently prepared from camphor and P^Sg 3**)» or bysaturating an alcoholic solution of camphor with hydrogen sulphide andhydrogen chloride. Unreacted camphor then can be removed by column chroma­tography over silica gel, using some alkane as an eluent3**, Thiocamphor,free from camphor, can also be prepared by treatment of camphor-diethyl-acetale32 with hydrogen sulphide under acid catalysis.Thiocamphor, photo-oxidation. Solutions of thiocamphor (2g) in iso-octane,benzene, CCl^ and CHCl^ (100ml) in a pressure bottle with oxygen wereirradiated during 4-8 hours with a high pressure Hg-lamp (500W, Philips.NaNO^f liter-) till the orange red colour had disappeared. The pressure inthe bottle was Kept at 4atm. during the reaction. It was shown by G.L.C.that the solvent did not influence the composition of the mixture ofreaction products: camphor was the main product (50%), three other products(together 7%) werB analyzed by mass spectroscopy as C^H^OS, C ^ H g0 and^20^28^' l=ormat:*-Pn of products insoluble in the reaction medium was alsoobserved. The stochiometry of this oxidation reaction has not beenestablished. It might be that oxygen reacts with a thioketone to giveketone and sulphur monoxide (SO). The latter is known to be a vigorousoxidizing agBnt33 which might attack the reactants thus decreasing theyield of desired product.+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +

Experiments concerning compound 7.Bornylacetate (8), oxidation. Procedures-^or the oxidation of bornyl-acetate with chromic anhydride have been given by various authors7 38 37 389). We used Asahina's procedure7 with two modifications: choice of a

83

h ig h e r r e a c t io n te m p e ra tu re , and a d i f f e r e n t is o la t io n p ro ce d u re ,

A m ix tu re o f 1- b o rn y la c e ta te (50g, A ld r ic h ) , a c e t ic a c id ('200ml) and

a c e t ic a n h y d r id e (100m l) in an 1 1 - f la s k p ro v id e d w ith s t i r r e r and the rm o­

m e te r i s hea ted to 8 5 °. Then C r03 (BOg) and a c e t ic a n h y d rid e a re added,

in 5g and 8 jm l p o r t io n s r e s p . , a t in te r v a ls o f 5 m in u te s . By o c c a s io n a l

c o o lin g th e te m p e ra tu re i s k e p t between 90 and 100°. A f t e r th e a d d i t io n . o f

a l l o f th e o x id iz in g a g e n t, s t i r r i n g i s c o n tin u e d t i l l th e te m p e ra tu re has

f a l l e n to 50 °. Most o f th e s o lv e n t i s removed a t a s p ir a to r p re s s u re . To th e

re s id u e i s added CH2C12 (3 0 0 m l); th e m ix tu re is r e f lu x e d on a w a te r ba th

f o r one h o u r , th e n th e in o rg a n ic m a te r ia l i s l e f t to s e t t l e , and th e sup e r

n a ta n t l i q u i d i s d e can te d . T h is p ro ce d u re is re p e a te d 4x w ith 100ml

p o r t io n s o f CH2C12 - The combined CH2C l2- e x t r a c ts a re n e u t r a l iz e d , f i l t e r e d

and d r ie d . (P ro b a b ly i t i s more c o n v e n ie n t to use steam d i s t i l l a t i o n tha n

e x t r a c t io n f o r th e is o la t io n o f th e re a c t io n p ro d u c t a f t e r th e o x id a t io n ) .

The s o lv e n t and th e b u lk o f u n re a c te d J3 were removed a t 15mm Hg, th e

k e to n ic e s te rs from th e o x id a t io n o f 8 (1kg ) were c a r e fu l l y f r a c t io n a te d

u s in g a N e s te r-F a u s t s p in n in g band column (2 m l/h o u r ; 120-30 /10mm H g).

5 1 .9g o f f r a c t io n s m a in ly c o n s is t in g o f 6 -ace toxycam phor (£ ) was th e n

o b ta in e d . To th e s e f r a c t io n s hexane (25m l) was addedj s to ra g e o f th e

r e s u l t in g s o lu t io n a t -2 0 ° a f fo rd e d c r y s t a l l in e £ (3 5 g ) . mp 49-57 .

C o n t in u a t io n o f th e d i s t i l l a t i o n u s in g a C la is e n d i s t i l l a t i o n head, and

r e c r y s t a l l i s a t i o n o f th e c r y s t a l l in e d i s t i l l a t e fro m hexane gave 6 -a c e to x y -

ep icam phor (£7 . f i g . 7 -1 7 ) . 136g, mp 6 0 -7 2 ° . N o te : 9 and 17 can a ls o be

se p a ra te d by p re p . G .L .C . (LAC co lum n) .

r ^ Y 0Accr03.O H j H A C

( A c ) 2 0

8

0JV+ 17 18

F ig u re 7 -1 7 : a b s o lu teo x \

% f r " 0 A c

c o n f ig u r a t io n s a red e p ic te d 1*6 .

19 9

6 -E n d o -a ce to xv -e p lca m p h o r (£7) was p u r i f ie d by p re p . G .L .C . (LAC colum n)

and r e c r y s t a l l is e d fro m hexane. Mp 7 2 . 5 - 4 . 0 ° , [ o ] D- 9 8 .5 ° (a b s . E tOH). L i t . :

mp 7 8 ° , [a ] - 8 7 .9 ° (E tO H )7 ; mp 78° . [ V ] D+B7.44° (E tO H )39 (o th e r a n t ip o d e ) .

6 -E ndo -ace toxy-cam phorqu inonB ( 1 8 ) . T o iv o n e n 's m ethod36 was used. From £7

(10g) and Se02 ( 5 . 3 g ) , hea ted w ith o u t s o lv e n t on an o i l ba th (155 , 1

h o u r ) , a f t e r r e c r y s t a l l i s a t i o n (4x ) fro m p e tro le u m e th e r 60-80 , was

84

o b ta in e d 1J3 (2 .8 g ) , mp 1 0 2 -4 ° , [a JD-1 8 7 .7 ° ta b s . EtOH). L i t . : mp 109°,

[ a ] D-1 9 1 .4 ° ta b s . EtOH)7 ; mp 1 0 3 -5 ° , [ a ] D-1 9 0 ° ta b s . E tO H)38.

6 -E n do -ace to xy -cam ph o r (9 ) had ne ve r been is o la te d b e fo re , a lth o u g h

A sah in a7 had p roved t h a t b o th 9 and _1_7 were fo rm ed on C rO ^ -o x id a t io n o f _8.

We proved th a t th e K e to n ic e s te r w h ich was s e p a ra te d fro m 17 by

d i s t i l l a t i o n had th e ass ign ed s t r u c tu r e (EH because S e 0 „ -o x id a t io n o f t h i s

e s te r gave th e same d ik e to n e C1B) as was o b ta in e d fro m 17.

The p u re s t sample o f £ , mp 6 0 .0 -1 .5 , [a ] + 44 .3 2 ° ta b s . E tOH), was o b ta in e d

a f t e r th e a tte m p te d p re p a ra t io n o f th e c o rre s p o n d in g N - is o p ro p y l im in e .

Under c o n d it io n s as used f o r th e p re p a ra t io n o f c a m p h o r-N -is o p ro p y lim in B 1*1

17 re a c te d w ith is o p ro p y la m in e and T iC l , in to lu e n e to g iv e ( in 70% y ie ld )

th e d e s ire d N - is o p ro p y l im in e , w h ich was shown by G .L .C . to be f r e e from

s t a r t in g m a te r ia l (1 7 ) . However, a f t e r th e r e a c t io n o f 9 (6 .0 g ) in th e same

manner was o b ta in e d a l i q u i d p ro d u c t (5 .4 5 g ) , m a in ly c o n s is t in g o f

u n re a c te d 9 . U s ing p re p . G .L .C . (SE-30 colum n) 9 was re c o v e re d , and a f t e r

r e c r y s t a l l i s a t i o n from hexane had p h y s ic a l c o n s ta n ts as in d ic a te d above.

6 -E n d o -h y d ro x y -e p lc a m p h o r. A m ix tu re o f X7_ C10g) and 10% K„C0 - s o lu t io n

(268m l) was r e f lu x e d f o r 5 h o u rs . P a r t o f th e 6 -e n d o -h y d ro x y -e p ic a m p h o r

(5g ) c r y s t a l l is e d on c o o lin g ( f in e n e e d le s ) . A n o th e r 2 .5 g c o u ld be removed

by f i l t r a t i o n a f t e r th e m o th e r - l iq u o r had been c o n c e n tra te d to 100m l. The

p ro d u c t was p u r i f ie d by r e c r y s t a l l i s a t i o n fro m hexane-benzene and

s u b lim a t io n . Y ie ld 6 .2 g , mp 2 4 3 .5 -5 .0 ° , [a ] ^ - 7 9 .0 ° (ab s . EtOH). L i t . :

mp 2 2 6 -3 0 ° , Tal + 6 4 .3 ° (a b s . E tOH)37 (o th e r a n t ip o d e ) ; [a ] + 7 1 .4 ° (E tO H )33u U u "* D

( o th e r a n t ip o d e ) .

6 -E n d o -h y d ro x y -e p lc a m p h o r-h y d ra z o n e . A m ix tu re o f _17 ( 4 .0 g ) , anhydrous

h y d ra z in e 1*2 (2 .4 3 g ) and a b s o lu te a lc o h o l (4m l) was r e f lu x e d f o r th re e

h o u rs . The c r y s ta ls o b ta in e d on c o o lin g were r e c r y s t a l l is e d fro m THF to

y ie ld 6 -e n d o -h y d ro x y -e p ic a m p h o r-h y d ra z o n e , 2 .1 g , mp 1 3 6 -4 3 ° . (The IR

spectrum o f th e re a c t io n p ro d u c t showed th a t h y d r a z in o ly s is o f th e e s te r

group o f 17 had ta k e n p la c e , as was e x p e c te d ) .

6 -E n do -hyd ro xy -cam p ho r-h yd ra zone was p re p a re d ana logue to th e p re p a ra t io n

o f 6 -e n d o -h y d ro x y -e p ic a m p h o r-h y d ra z o n e . S in ce no c r y s t a l l i s a t io n to o k p la c e

on c o o lin g o f th e re a c t io n m ix tu re , i t was e v a p o ra te d to d ry n e s s .

R e c r y s ta l l is a t io n o f th e re s id u e from benzene th e n gave 6 -e n d o -h y d ro x y -

cam phor-hydrazone , mp 8 5 -9 0 ° .

A tte m p ted p re p a ra t io n o f c h e m ic a lly pu re 6 -e nd o -h yd ro xy -ca m p h o r (1 1 ) .

85

Although 6-hydroxy-fenchone has been prepared by saponification of thecorresponding benzoate**^ we failed to prepare pure 11 from 9.- A mixture, of 9_ (1.5g), alcohol [3.5ml) and KOH (0.7g) was refluxed for

2.5 hours. The mixture turned deep red. The alcohol was removed. When theresidue was neutralized after ether had been added, the colour changed toyBllow. The ethereal layer was separated; the organic material(1.1g) obtained on evaporating the ether, did not crystallise. Steamdistillation of this product gave a water-insoluble, non volatile residue(0.6g) and no yield because no CO could be measured of a sample of the(homogeneous) distillate.

- A mixture o f £ (1.0g) and 1G% K CO^-solution (27ml) was refluxed for 5hours. Again, evaporation of the ether extract gave no crystallineproduct.

- A mixture of 6-endo-hydroxy-camphor-hydrazone (0.9g), cone. HC1 (1.35g)and ethylene chloride (6.5ml) was refluxed for 17 hours. From G.L.C.-measurement of the brownish-red solution it was then deduced, that theyield of 11 was low. (Under similar conditions camphor-hydrazone (0.82g)was hydrolysed to give camphor (0.7g)).

- A mixture of 9 (1.0g), JN HC1 (1ml) and dioxane (2ml) was refluxed for22 hours. Then G.L.C.-measurements (SE-3Q column) showed that 9 hadalmost disappeared from the mixture. Three products with a retention timeshorter than 11 were formed; the most abundant product (,v84%) wasanalyzed by mass spectroscopy as C.nH.o0_ (11). But again, an oil was1U 1b c. ■*—obtained from the ethBr-extract of the reaction mixture. Isolation of 11from the. mixture, using prep. G.L.C., has not been attempted.

Attempted preparation of the diethyl-acetale of 6-endo-acetoxy-camphor (j ).Camphor-diethy1-acetale has been prepared in two different manners in theliterature: from camphor and orthoformic acid-triethyl ester**1* **5, and bytreatment with sodium ethanolate of O-ethy 1-camphor-oxonium-fluoborate** ,which can be prepared from camphor and triethyl-oxonium-fluoborate. Thelatter method is superior by far. Both methods have been tried for thepreparation of the diethyl-acetale of 9.- A mixture of 9 (4.0g), orthoformic acid-triethyl ester (5ml), super dry

alcohol (6ml) and concentrated H SO^ (0.1ml) was lBft to stand at roomtemperature. The reaction was followed by G.L.C. (1% OV-17 column). Onlyproducts were formed with a retention time shorter than the retentiontime of 9. After a few days two of the reaction products were isolated

86

by G.L.C. and analyzed by mass spectroscopy, but none was the desiredacetale of £ or the corresponding enol-ether.Because the available quantity of 17_ was larger than the quantity of 9,first the preparation of an acetale via an O-ethyl-oxonium-fluoborate wasattempted from 17» The procedure for the preparation of the correspondingcamphor derivative1*7 was used when the preparation of the O-ethyl-fluoborate of X7_ was attempted.Initially the mixture of _17 (6.B3g) and triethyl-oxonium-fluoborate(6.2g)“*8 in methylene chloride (9ml) consisted of two layers, but afterstanding for 1.25 hours it was homogeneous. However, the reaction productdid not crystallise, as does O-ethyl-camphor-oxonium-fluoborate, not evenwhen the mixture was stored at -15°. The residue, obtained on evaporationof the solvent, was a viscous liquid, which on treatment with analcoholic solution of sodium ethanolate did not give an acetale. This wasdeduced from G.L.C., and from the faillure of the reaction product togive the pink colour of a thioketone on treatment with H2S under acidcatalysis.After this negative result the preparation of the acetale of 17 was notattempted in the same manner.

Attempted preparation of the thioketone corresponding to 6-endo-acetoxy-camphor (9_) ■ Preparation of the thioketone corresponding to 6-endo-acstoxy-*epicamphor (17) presented no difficulty: as was shown by G.L.C. and massspectroscopy this was thB only reaction product when 17. (4.0g) was refluxedwith P2S 5 t3.5g) in toluene (40ml) for three hours.The same thioketone together with its hydrolysis product 6-endo-hydroxy-thioepicamphor was formed when in an autoclave a mixture of 17 (3.95g) "witha solution of HC1 (2.1g) in absolute alcohol (15.3g) and H2S was left tostand at room temperature for four days. (H S has been introduced into theautoclave by connecting a lecture bottle to the closed autoclave, and then-opening both taps). These thioketones were not purified.

Preparation of the thioketone corresponding to 6-endo-acetoxy-camphor(£) presented difficulties. The reaction product from 9 (4.0g) and asolution of HC1 (2.4g) in absolute alcohol (15.25g) in an autoclave(3 days) as above, partially consisted of pink polymeric material whichwas visible in thB glass G.L.C.-column (1% SE-30) after the analysis of themixture. The main (volatile) product was not the desired thioketone asfollowed from mass spectroscopic measurements.

87

The experiments with P_Sj- were no succesful either:- A mixture of 9 [4.0g), P2S5 C3.5g) and toluene (40ml) is refluxed for2.7 hours. Then the mixture is brown whereas it should be red. G.L.C.(glass 1% SE-30 column) shows that at least 3 products are formed, butin low yield.

- A mixture of 9 (0.9g), (0.85g) and toluene (9ml) is refluxed for 5hours. The mixture then is dark brown. But now the relative yield of oneof the reaction products is higher than in the previous experiment, whichsuggests that the other products are thermally less stable-. The mainproduct was isolated by G.L.C. and analyzed by mass spectroscopy asC H 0 S (i.e. the composition of the desired product).A solution of the reaction products in CCl^ was irradiated in the visibleregion till the red colour had disappeared, while oxygen was bubbledthrough the mixture. Then a gaschromatogram of the colourless solutionshowed, that the peaks of the reaction products, except for the peak ofthe main product, had disappeared. Thus the main product, being colour­less, could not be a thioketone.

Conclusion from the experiments on 2,6-diketo-camphane (7).Because of the unavailability of derivatives (N-isopropylamine, acetale,thioketone) of 6-endo-acetoxy-camphor (9.), suited for the introduction ofthe 180-label by hydrolysis, the only way left for the praration ofspecifically labeled 2,6-diketo-camphane (7) from (9_) (fig. 7-17) seems tobe to label £ by exchange, then to remove the ester group by reduction, andto oxidize the diol 1£ obtained. But we havB not yet verified whether theoxidation of an 180-alcohol can be carried out with retention of label.+ + t + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +

Experiments concerning compound 23 ** ).4-Cvclohexene-1,2-dimethanol-ditosylate (21.). The preparation of 2± from4-cyclohexene-1,2-dicarboxylie acid is described in chapter 5.4-Cvclohexene-1,2-diacetonitrile. Cope’s procedure50 for the preparationof a nitrile from a tosylate with KCN in DMSO was used to obtain 4-cyclo-hexene-1,2-diacetonitrile from 2£. After the volume of the reaction mixturewas doubled by the addition of water, the dinitrile was isolated51 byextraction with an equal volume of benzene, divided over 5 portions. Theextract was dried with water, dried and evaporated to give the crudedinitrile, mp 76-9°, (lit.52: mp 79.5-00.5°), in 90% yield.

88

4-Cyclohexene-1,2-diacetlc acid. The above dinitrile (176.5g) was refluxedwith KOH (176.5g), alcohol (243ml) and water (567ml) for 24 hours. Thecrystals which precipitated on addition of cone. HC1 were recrystallisedfrom water to give the diacetic acid (167.6g, i.e 77%), mp 183-9 . Lit.5 :mp 199-200°.Hydrindenone (22). A standard procedure53 was used for the decarboxylationof 4-cyclohexene-1,2-diacetic acid. The crystalline product was dissolvedin ether and washed with a bicarbonate solution till free from acid. Onevaporation of the ether 22^ mp 57-63°, was obtained in only 59% yield.Recrystallisation from heptane raised the mp to 67.5-B.80. 22_ gave a semi-carbazone, mp 218-22° (d) (recrystallised from alcohol).Hydrindenol. To a stirred solution of 22 (32g), A.R. MeOH (50ml) and water(35ml) was added dropwise a solution of NaBH (6g) and NaOH (5g) in water(35ml). The temperature was kept between 40 and 50° during the addition.After the addition the reaction mixture was kept (with stirring) at 50(24 hours) till only a trace of 22 was left (G.L.C.). Then the reactionmixture was poured into water. The crystalline alcohol was dissolved inether and shaken with a saturated NaHSO^-solution. Evaporation of the ethergave hydrindenol in 84% yield.Hydrindenylacetate (24). Hydrindenol, treated with acetic anhydride inpyridine, gave 2 4 in 93% yield.Attempted ring opening of the blcyclor4.3.0*lnonene skeleton of 22 and 24.- Cope's procedure51* for the ring opening of bicyclo£7.1.ojnonene withKMnO. in acetone was used for the oxidation of 22_ (25g), but no yield wasobtained. When after the reaction the solvent was evaporated, using arotatory evaporator, rather unexpectedly some unreacted ketone (7.8g) wasrecovered. Presumably selective oxidation of the double bond in 22_ is notpossible by this method.

- Cope 's procedure5** was then used for the oxidation of 24; only a pooryield was obtained.

- An ozonisation procedure55 was used for the oxidation of 24. ThB productwas not (NMR, mass spectroscopy) the desired di-aldehyde.

3,4-Epoxy-trans-bicyclor4.3.0*1 nonane-8-ol-acetate (25) was preparedanalogue to the preparation of 1,2-epoxy-cyclohexane from cyclohexene 6.Yield 85%, mp 40-50°, bp_ 113-7°. The peracetic acid used for thisepoxidation was prepared5 from boric-acetic-acid anhydride5® and cone,hydrogen peroxide59.

89

Oxidation of 25 with DMSO. Cohen and Tsuji60 have reported that epoxidescan be oxidized with DMSO in the presence of a catalytical amount of BF„-ether complex to give acyloins in good yield.First we attempted oxidation of 1,2-epoxycyclohexane56 and found (G.L.C.)that under the conditions of 66) not all of the epoxide was oxidized. MoreBF_-complex was. then added and the reaction was continued till all -of theepoxide had disappeared. A high yield of acyloin was obtained. 25 wasoxidized in the same manner60; again more BF„-complex had to be added toachieve complete oxidation. The reaction product [26], obtained inquantitative yield by CHCl^-extraction after the reaction mixture had beenpoured on ice, was a viscous liquid.Oxidation of the crude acyloin (26). Rigby’s method61 was used for theoxidation of 26. A mixture of H®*4g) and acetic acid (30g) wasrefluxed for 2.5 hours. Then the acyloin (26, 18.3g) was added and heatingwas continued on a bath at 100 for 1 hour. The mixture was filtered andthe precipitate washed with CH Cl^. The solvent of the filtrate wasevaporated; a green coloured impurity of the residue could be removed byoolumn chromatography, (silicagel, ether). Yield 18g. This product was shownby NMR to contain polymeric material. Distillation of the product andrecrystallisation of the distillate from heptane-toluene gave 7J_, 4..2g,mp 119.8-21.4°. Presumably milder reaction conditions are necessary if.onewants to-prepare 27_ from 26_ in an reasonable yield. Mild oxidation ofacyloins seems to be possible62 using Pb(0AcK.Attempted resolution of 22 with "menthydrazlde". For preparation of thederivative of 22 with ’’menthydrazlde” 11+) the procedure for the preparationof the corresponding derivative of a-ionone62 was used. After refluxing for12 hours the solvent was removed and the residue dissolved in n.-heptaneand filtered while hot. Yield 7.6g (from 5g of 22), mp 135-6 . Regenerationof this derivative gave 22, small negative Cotton effect, optical purity4.5% 61f).Attempted resolution of 22 with 4-(endo-2-fenchyl)-semicarbazide.A mixture of 22 (5g), 4-(endo-2-fenchyl)-semicarbazide*p.-toluenesulphonicacid (15i2g), NaOAc'SH^O (6.8g) and alcohol (150ml) was refluxed for 12hours. The crystals obtained on cooling were recrystallised from alcohol.Yield 7.45g, beautiful needles, mp 219-25 . Regeneration of the derivativegave 22, small negative Cotton effect, optical purity 2.3% 6 .).4-(Endo-2-fenchyl)-semicarbazide•p.-toluenesulphonic acid.

90

The procedure of Goodson65 for the preparation of 4-alkyl-substitutedsemicarbazides was used to prepare 4-(endo-2-fenchyl)-semicarbazide*p.-toluenesulphonic acid from fenchylamine.- Endo-2-fenchylamine. Crude fenchylamine (see chapter 2) was shown byG.L.C. to be a mixture of two compounds, as was expected (partialseparation with a Carbowax column). The minor component of this mixturecould be removed by recrystallisation of the amine-hydrochloride fromdioxane (2x). The assignment of the endo-configuration to the stericallypure amine is based on the stereochemistry of reductions with sodium andalcohol in the norbornane series.

- 4-(Endo-2-fenchyl)-acetone-semlcarbazone was prepared65 by addition ofacetone-semicarbazone to heated endo-2-fenchylamine. Yield 63% (afterrecrystallisation from alcohol), mp 205-10°.

- Hydrolysis of 4-(endo-2-fenchyl)-acetone-semicarbazone with hydrochloricacid65 was unsatisfactory because the hydrochloride of 4-(endo-2-fenchyl)-semicarbazide was found to be good soluble in water. The hydrolysisexperiment was repeated with p.-toluenesulphonic acid of about the sameconcentration as the hydrochloric acid used in the previous experiment.A toluenesulphonic salt crystallised on cooling of the reaction mixtureafter the hydrolysis, but it was found to be reasonably soluble in water,thus concentration of the mother-liquor was necessary to improve theyield.

Oxidation of a-hydroxy-cyclopentane-carboxylic acid. a-Hydroxy-cyclo-pentane-carboxylic acid was prepared66 by hydrolysis of cyclopentanonB-cyanohydrine6'.In a round-bottommed flask, provided with a distillation head, was heateda mixture of PbO^ (32g), a-hydroxy-cyclopentanone-carboxylic acid (10g)and water (100ml). After the evolution of carbon dioxide had stopped, morewater was to the reaction mixture, and then a mixture of cyclopentanoneand water ('vlOOml) was removed by distillation. The cyclopentanone in thereceiver was precipitated as the semicarbazone. For comparison thetheoretical amount of cyclopentanone, that could have been formed in thisoxidation, was dissolved in water (100ml) and then precipitated as thesemicarbazone. Comparison of the weights of the two portions of semi-carbazones indicated that the yield in the oxidation reaction was 87%.

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +

91

wasExperim ents concern ing compound 35 **9 ) .[1 s : 3s : Br: 10r ) - T r i c y c l o f S . 4 ■ 0 . 0 3 ' 8~l t e t r a d e c a - 5 , 1 2 - d i e n e - 2 , 9 - d i o n e [29 )

prep a re d from p . -benzoquinone and b u ta d ie n e in t o l u e n e 15, and was

r e c r y s t a l l i s e d from to lu e n e . Mp 137°; l i t . 15 : 154-5 .[1s :3 r : Br: 1 0 s ) - T r i c y c l o p . 4 . 0 . 03‘ 81 t e t r a d e c a - 5 ,1 2 - d l e n e - 2 ,9 - d io n e [30).

The p u r i f i e d d ik e to n e 2£ was d is s o lv e d in a l c o h o l , and t o t h i s s o lu t io n

w hile hot was added an a l c o h o l i c s o lu t io n o f po tass ium h y d rox ide15. Thep roduc t [30) was p u r i f i e d by r e c r y s t a l l i s a t i o n from THF o r e t h y l a c e t a t e .

Mp 241-2» l i t . 15 : 244 -5° .[1s : 3 r : 8 r : 10s ) - T r i c y c l o f a . 4 . 0.O3 ' 8! t e t r a d e c a - 5 , 12- d i e n e - 2 , 9 - d i o l (31_). The

d ik e to n e 31 (257g) was added, u s in g a S o x le th , t o a m ix tu re of LAH (60g)

and THF (3 1 ) . A f te r th e re d u c t io n most o f th e THF was removed by

d i s t i l l a t i o n and r e p la c e d by e t h e r . 31_ was found t o be on ly s l i g h t l yso lu b le in e t h e r . A f te r c a r e f u l a d d i t io n o f w a te r t o th e r e a c t io n m ix ture

t o d e s t ro y th e u n re a c te d LAH, enough i c e and cone. HC1 was added t o perm it

i s o l a t i o n o f 31 by f i l t r a t i o n . Y ield 94%. This d i o l was no t p u r i f i e d .P i t o s y l a t e o f 31 (3 2 ) . T h is d i t o s y l a t e was p repa red from 31_ u s in g H i l l ’s

p ro c e d u re 6 8 . The crude p r o d u c t , p rep a re d in B6% y i e l d , was brown. The

co lo u re d im p u r i ty could be removed by b o i l i n g th e c r y s t a l s w ith n . -b u ta n o l»

t h e c r y s t a l s were th e n removed by f i l t r a t i o n when th e m ix tu re was coo led .(1 s : 3 r :8 r : 1 O s ) - T r l c y c lo r B .4 .0 .0 3 ' 8l t e t r a d e c a - 5 , 1 2 - d i e n e (3 3 ) . C r o s s l e y ’s

p ro c e d u re 15 f o r t h e p r e p a r a t io n o f 33 by LAH re d u c t io n o f 32 was used with

some m o d i f i c a t i o n s . I t was not n e c e s sa ry t o use a S o x le th f o r th ei n t r o d u c t io n o f 32 in th e r e a c t io n m ix tu re : a l l o f 32 could be added a t

once» th e re d u c t io n i s slow because o f t h e very low s o l u b i l i t y o f 32 in

b o i l i n g THF. We r e f lu x e d f o r 7 days , then most o f th e THF was removed by

d i s t i l l a t i o n , and w a te r was c a r e f u l l y added. 33 could be removed by f i l ­t r a t i o n a f t e r th e r e a c t io n m ix tu re had been made s t r o n g ly a c id w ith cone.

HC1. 33 was p u r i f i e d by s u b l im a t io n [95°, 2mm Hg). Y ie ld 70-75%, mp 108.0-10, 5°» u t . 15: mp 112-3°. We n o t ic e d t h a t a brown im p u r i ty was formed on

s t o r i n g o f 33» t h i s im p u r i ty i s p robab ly an a u to x id a t io n p ro d u c t .(1s : 2 s : 4r : 5 r )-C y c lo h ex an e- 1 , 2 , 4 , 5 - t e t r a - a c e t i c a c id (3 4 ) . A f t e r a t tem p ts t o

p r e p a re p re p a re 3£ from 33 by o z o n i s a t io n (0 ° . CC14 and C C l^ e th y l a c e t a te )

had been g iven up because in s o l u b le ozon ides were formed. Cope’s p rocedure

5l1) f o r t h e o x id a t io n o f b ic y c lo [ 6 .1 .o]nonene was used t o g ive 34 in 22%

y i e l d . Mp 290-5° (d) a f t e r r e c r y s t a l l i s a t i o n from w ate r .

92

(1 s : 3 r : 7 r : 9 s ) - T r i c y c l o p . 3 . 0 .0 * 2 3 * 5 6‘ 7 * 9 10 * 12 131 dodec a n e -5,11 -d io n e ( 35 ) . The u s u a l

p ro c e d u re 63 f o r th e p re p a ra t io n o f a Ketone fro m a d ic a r b o x y l ic a c id was

used, bu t now th e d e ca rb o xy la tio n was donB a t 15mm. The d ike tone 3S_, mp

2 1 5 -6 ° , was o b ta in e d in 41% y ie ld ( a f t e r r e c r y s t a l l i s a t i o n fro m a lc o h o l) .-1 -135 has i t s C = 0 -s tre tc h v ib r a t io n a t 1730cm (KBr p e l l e t ) , and a t 1739cm

(CHC1_). From e m p ir ic a l r u le s 69 i t f o l lo w s t h a t th e c a rb o n y l group i sd 13a tta c h e d t o a 5-membered r in g . There i s a ls o an e m p ir ic a l r u le in C-NMR

13s p e c tro s c o p y 70 w h ich r e la te s th e C - s h i f t o f th e carbon atom fro m th e13c a rb o n y l group t o th e r in g s iz e . The C - s h i f t s (w ith re s p e c t t o CS ) o f

carbon atom fro m th e c a rb o n y l group o f cyc lo he xano ne , cyc lo pe n tan one and

35 a re ra s p . -16ppm, -26ppm and -23 .8ppm ( in CHC1_). Thus in v ie w o f t h i s13 de v ide nce fro m IR and C-NMR we can s ta te t h a t o u r d ik e to n e has in d e e d

s t r u c tu r e and n o t Jl6 ( f i g . 7 - 8 ) .

+ + + + + + + + + + + + + + + + + + + +..+ + + + + + + + + + + + + + + +. + '+

R e fe re n c e s .

* ) D. Sadeh and □. Sam uel, I s r . J . Chem., 1_, 251 (1 9 6 3 ).

2 ) M. B ym and M. C a lv in , J . Amer. Chem. S o c ., 88 , 1916 (1 9 6 6 ).

P. G re e n za id , Z. Luz and D. Samuel, T ra n s . F a ra d . S o c ., 2787 (1 9 6 8 ).

3) See c h a p te r 2 , r e f . 92 ) .

9 ) R. S r in iv a s a n and W.A. Noyes, J r . , J . Amer Chem. S o c ., 82 , 5591 (1 9 6 0 ).

5 ) See: J .L . S im onsen, The T e rpe ne s , Cambridge U n iv e r s i ty P re s s , 2nd e d . ,

v o l . 2 , 438 (1 9 4 9 ).

6 ) F o r exam ple b u t y r i c a c id does n o t exchange oxygen when hea ted w ith

la b e le d w a te r (1 0 0 ° , 24 h o u rs ) . C f. 0 . R e iz , Z . E le k tro c h e m ., 4 5 ,

106 (1 9 3 9 ).

7 ) Y. A sah in a , M. I s h id a te and T . Tukam oto, B e r . , 69^, 349 (1 9 3 6 ).

° ) N o te : p re p a ra t io n o f la b e le d J_1_ by exchange i s o n ly u s e fu l i f i t can be

shown th a t 11 does n o t racem ise v ia a t r i c y l i c e n o l fo rm under

c o n d it io n s as used f o r th e la b e in g .

9 ) F. Leyendekke r, G. M a n d v ille and J .-M . C o n ia , B u l l . Soc. Chim. F r . ,

556 (1 9 7 0 ).

10) W.C.M.C. Kokke, u n p u b lis h e d r e s u l t s .

n ) 0 . W a lla c h , A n n ., 437, 148 (1 9 2 4 ).

12) C f. Houben-W eyl, Methoden d e r O rgan ischen Chemie, Georg Thieme V e r la g ,

S t u t t g a r t , v o l . 8 , 454 (1 9 5 2 ).

13) A. M c K illo p and J .D . H u n t, T e tra h e d ro n L e t te r s , 5245 (1 9 7 0 ).

93

I1») R.B. Woodward, T.P. Kohman and G.C. Harris, . J. Amer. Chem. Soo.,63, 120 (1941).

15) N.S. CrosslBy and H.B. Henbest, J. Chem. Soo., 4413 (1960).16) Cf. Beilsteins Handbuch der Organischen Chemie, Springer Verlag,

Bd 7111, 3625 (1969).17) D.E. Bays, R.C. CooKson and S. Mackenzie, J. Chem. Soo. B, 3, 215

(1967).18) /\t least dehydronorcamphor is sufficiently stable to acids that it

can be regenerated from its semicarbazone, cf. K. Alder and -H.F. Rickert, Ann., 543. 19 (1940).

19) M. Saito, A. Endo, T. Nanko, H. Miki and Y. Fushizaki. J. Chem. Soc.Japan, Ind. Chem. Section, £3, 2003 (1960).

29) Org. Synth., vol. 51, 66.21) J. Meinwald and P.G. Gasman , J. Amer. Chem. Soc., 82_, 5445 (1960).22) F.T. Bond, H.L. Jones and L. Scerbo, Tetrahedron Letters, 4685 (1965).23) There are various patents for the preparation of 52 by ozonisation of

a-pinene (50), cf CA:jj7_ P696g, P2266c .An alternative for the preparation of 52 is Rosenmund reduction ofpinonic acid (51), cf. J. Kulesza and B. Wojtkiewicz, Roczniki Chem.,

40, 131 (1966).Note: optically pure a-pinene [50) to be used for the* preparation of 52_is best prepared by the isomerisation of 8-pinene (46), cf.R.L. Settine, J. Org. Chem., 35 , 4266 (1970); G.A. Rudakow andH.M. Shestaeva, Zhur. Obsch. Khim., 26_, 2357 (1956).

24) A. Zabza and H. Kuczynski, Roczniki Chem., 40_, 463 (1966).25) Org. Synth., vol. 42, 36 (1962).26) 58 is known to polymerize rapidly in alkaline solution, cf. C.H. dePuy

and E.F. Zaweski, J. Amer. Chem. Soo., 81_, 4920 (1959).27) E.J. Corey and M. Chaykovsky, J. Amer. Chem. Soc., 84, 867 (1962)»

87_, 1353 (1965).

28) A. Yogev, J. Heller and A.S. Dreiding, Chimia, 23, 411 (1969).29) W.C. Howell, M. Ktenas, J.M. MacDonald, Tetrahedron Letters, (1964)

1719.'

30) E.J. Corey and H.J. Burke, J. Amer. Chem. Soo., 78 , 174 (1956).É.J. Corey, H.J. Burke and W.A. Remers, J. Amer. Chem. Soc., 78 , 174

(1956).

94

J .R .B . C am pbe ll, A.M. Is la m and R .A . R aphae l, J . Chem. S o c . , (1956)

4096.

G .L . Buchanan, R .A. Raphael and I .W .J . S t i l l , J . Chem. S o c ., (1963)

4372.

31) H. W uyts, B e r . , 36 , 8 6 3 .(1 9 0 3 ).

32) R. M ayer, J . M orgens te rn and J . F a b ia n , Angew. Chem., 76 , 157 (1 9 6 4 ).

33) G. O s te r , L . C i ta r e l and M. poodman, J . Amer. Chem. S o c ., 84 , 703

(1 9 6 2 ),

31*) C.A. Em eis, t h e s is Le iden (1 9 6 8 ).

35) G m elins Handbuch d e r A norgan ischen Chemie, V e r la g Chemie, 8. A u f l . ,

Bd 9B1, 171 (1 9 5 3 ).

36) N .J . T o ivo n e n , P. H i r s ja r v i , A. M e la ja , A. K a in u la in e n , A. Halonen and

E. P u lk k in e n , A c ta Chem. S can d ., 3 , 991 (1 9 4 9 ).

37) P. M alkonen, Ann. Acad. S c i. F e n n ica e , A l l 128, 25 (1 9 6 4 ).

38) J . M e inw a ld , J .C . S h e lto n , G .L . Buchanan and J .A . C o u r t in , J . Org.

Chem., 33 , 99 (1 9 6 8 ).

33) J . B re d t and A. Goeb, J . P ra k t . Chem., n .F . 101, 273 (1 9 2 1 ).

**°) 1 -B o m y la c e ta te (8 ) can be c o n v e rte d in t o ( - ) -c a m p h o r (19) o f known

a b s o lu te c o n f ig u r a t io n . C f. M.G. N o r th o l t and J .H . Palm , Rec. T ra v .

C h im ., 85 , 1 4 3 ,(1 9 6 6 ).

1*1 ) H. W e in g a rte n , J .P . Chupp and W.A. W h ite , J . O rg. Chem., 32 , 3246

(1 9 6 7 ).

**2 ) F. R a sch ig , B e r . , 43 , 1927 (1 9 1 0 ).

1>3) H. S ch m id t, M. M Q h ls tad t and Phom Son, B e r . , 99 , 2736 (1 9 6 6 ).

I | lt) M. B re d t-S a v e ls b e rg and C. R um sche id t, J . P ra k t . Chem., n .F . 115 , 235

(1 9 2 7 ).

1>5) A. A rbu sov . J . Russ. Phys. Chem. S o c ., 61_, 1595 (1 9 2 9 ).

’ ®) Houben-W eyl, Methoden d e r O rgan ischBn Chemie, Georg Thieme V e r la g ,

S t u t t g a r t , Bd 6 /3 , 362 (1 9 6 5 ).

**7 ) H. M eerw ein, G. H in z , P. Hofmann, E. K ro n ig and E. P f e i l , J . P ra k t .

Chem., n .F . 147, 284 (1 9 3 7 ).

* • ) R e f. 1*5 ) , p 336.

<t3) T h is p a r t o f th e w ork was done in c o -o p e ra t io n w ith

M r. F .A . V a rk e v is s e r .

50) A .C . Cope and A .S . M ehta, J . Amer. Chem. S o c ., 86_, 5626 (1 9 6 4 ).

®*) C ope's is o la t io n p ro ce d u re was im proved by M r. J .C .A . W ind ho rs t in t h i s

d e p a rtm e n t.

95

52) D.C. Ayres and R.A. Raphael, J . Chem. S o c . , [19583 1779.

53) Org. S y n th . , C o l l . Vol. 1 , 192.5lf) A.C. Cope, Sung Moon and Chung Ho P a rk , J . Amer. Chem. S o c . , jJ4, 4843

(1962).

55) This p ro ce d u re , which has not been p u b l i s h e d , was developed a t S h e l l

Reseach in Amsterdam f o r th e a n a l y t i c a l d e te rm in a t io n o f double bonds

in open cha in a lk e n e s .56) J . BSseken and G.C.C.C. S c h n e id e r , J . P r a k t . Chem., n .F . 131, 287

(1931).

57) J . d'Ans and W. F rey , B e r . , 45 , 1851 (1922).58) A. P i c t e t and A. G e le zn o ff , B e r . , 3E[, 2219 (1903).59) G. B rau e r , Handbuch d e r P ra p a r a t iv e n Anorganischen Chemie, 2 . A u f l . ,

Enke S t u t t g a r t (1960), Bd 1, p 139.

60) T. Cohen and T. T s u j i , J . Org. Chem., 26_, 1681 (1961).

61) W. Rigby, J . Chem. S o c . , (1951) 793.62 ) R.E. P a r t c h , T etrahed ron L e t t e r s , (1964) (41) 3071.

63) Y.-R. Naves, Helv. Chim. Acta , 30 , 769 (1947).64) O p t ic a l ly pure 22 has been p rep a re d by Mr. J .C .A . Windhorst in t h i s

d epa r tm en t , th u s th e o p t i c a l p u r i t y o f our ketone fo l lo w s from

comparison w ith h i s d a ta .65) J . A. Goodson, J . Chem. S o c . , (1927) 1998.

66) B. Tchoubar and C. C o l l i n , B u l l . Soc. Chim. F r . , (1947) 680.

67) A.H. Cook and R.P. L in s te a d , J . Chem. S o c . , (1934) 958.68) R.K. H i l l , J .G . Martin and W.H. S touch , J . Amer. Chem. S o c . , 83, 4006

(1961).

69) K. N a k a n ish i , P r a c t i c a l I n f r a Red S pec tro sc o p y , Holden Day I n c . ,San F ra n c isc o (1962).

70) We got t h i s in fo rm a t io n from Dr. J.W. de Haan, T echn ica l U n iv e r s i ty ,

Eindhoven, who measured th e 13C-NMR spectrum o f 35.

96

SAMENVATTING

Het uitgangspunt voor het in dit proefschrift beschreven onderzoek wasde verwachting, dat meting van circulair dichroïsme van verbindingen, diealleen optisch actief zijn door isotopensubstitutie, nieuwe en nuttigeinformatie zou kunnen geven over de electronenstructuur van dezeverbindingen.

Omdat effecten in optische activiteit ten gevolge van isotopensubstitu­tie byzonder klein zijn vergeleken met effecten in optische activiteit van(bv.] natuurstoffen, was het niet verwonderlijk dat nooit eerder CO vaneen dergelijk type optisch actieve verbinding gemeten was. De mogelijkheiddeze kleine effecten te meten hangt af van een gelukkige keuze van de temeten verbinding èn het beschikbaar zijn van een gevoelig CD aoparaat. Opde Afdeling Theoretische Organische Chemie is aan het tweede vereiste vol­daan doordat Drs. H.P.J.M. Dekkers voor zijn promotie-onderzoek een derge­lijk apparaat gebouwd heeft.

In hoofdstuk 1 van dit proefschrift wordt duidelijk gemaakt waarom hetwenselijk is aan isotopengesubstitueerde carbonylverbindingen te werken alsmen een redelijke kans wil hebben ook CD van zo'n verbinding te meten.

In de twee daarop volgende hoofdstukken zyn de syntheses beschreven van16 16( 0, °0)-a-fenchocamphoronchinon en 1-deutero-a-fenchocamphoronchinon,

verbindingen, welke een meetbaar effect in CD bleken te vertonen.Het overige beschreven werk, behalve het laatste hoofdstuk waar twee

methoden voor de bepaling van optische zuiverheid gegeven zijn, houdt hier­mee verband. In hoofdstuk 4 is op grond van absorbtie- en CD-metingen aaneen aantal norkamferchinonen geconcludeerd, dat de interpretaties in deliteratuur van het CD-spectrum van kamferchinon aan ernstige bedenkingenonderhevig zijn. In de appendix wordt een verantwoording gegeven over on-

16 16voltooid werk aan 0- 0-diketonen en wordt de synthese van een aantalinteressante diketonen voorgesteld. Het werk aan trans-1,2-dimethylcyclo-pentaan, beschreven in hoofdstuk 5, houdt verband met één van de onvoltooi­de projecten in de appendix, en bovendien met een recente publicatie overhet voorkomen van optisch actief 1,2-dimethylcyclopentaan in een ruwe olie.Van de in het laatste hoofdstuk beschreven methoden voor dé bepaling vanoptische zuiverheid berust de ene op het gebruik van circulaire polarisatievan de luminescentie (CPU j de andere op de fotochemische ontleding vanoptisch actieve verbindingen.

« * % * % * % %97

CURRICULUM VITAE

Na het behalen van het diploma H.B.S.-b aan het St. Stanislascollege inDelft begon ik in 1962 met de scheikundestudie aan de Rijksuniversiteit inLeiden. Het candidaatsexamen (letter F)' werd in december 1964 afgelegd.Daarna werd de studie voortgezet met Theoretische Organische Chemie alshoofdvak (bij Prof. L.J. Oosterhoff)j als bijvak werd Numerieke Wiskundegekozen (bij Prof. G. Zoutendijk) en als derde richting TheoretischeNatuurkunde (bij Prof. P.W. Kasteleyn). Na het doctoraalexamen, dat inseptember 1967 werd afgelegd, stelde Prof. L.J. Oosterhoff me in staat bijhem promotie-onderzoek te verrichten op het gebied van de optische activi­teit, een onderwerp waarvan ik de synthetische aspecten al had leren kennentoen ik tijdens mijn hoofdvakstudie meehielp aan een deel varr het promotie­onderzoek van Dr. C.A. Emeis.Van 1 October 1967 tot 1 maart 1972 was ik als wetenschappelijk medewerkerin dienst bij Z.W.O.j vanaf 1 maart 1972 ben ik als wetenschappelijkmedewerker 1e klasse in dienst bij de Rijksuniversiteit in Leiden.

Proefschriften komen niet tot stand zonder de medewerking van een grootaantal anderen zoals het niet-wetenschappelijk personeel van het Gorlaeus.Laboratorium. Van deze mensen wil ik met name danken de Heren amanuensesvan de 6e verdieping, de Heren glasinstrumentmakers, en de Heer B. v. Vlietvan de afdeling gaschromatografie, voor de wijze waarop ze hulp boden, alsop hen een beroep gedaan werd.De prettige samenwerking met de heren Drs. J.C.A. Windhorst enF.A. Varkevisser heb ik zeer op prijs gesteld. De laatste heeft ook daad­werkelijk hulp verleend bij mijn promotie-onderzoek.Als Drs. H.P.J.M. Dekkers niet een gevoelig CD-apparaat gebouwd had, washet onmogelijk geweest CD te meten van de isotopengesubstitueerdea-fenchocamphoronchinonen.De tekeningen in dit proefschrift werden verzorgd door de heren M. Pisonen J.J. Pot.

% % % % % % % % % % - % % % % % % % % % % % % % % % % % % % % % % % % % % % %

96

STELLINGEN

1/ Alvorens grotere hoeveelheden van een organische verbinding metruthenium tetroxide te oxyderen is het wenselijk de reactie eerst opkleine schaal uit te voeren in aanwezigheid van een inerte ijkstof.

2/ De bewering, dat bij autoxydatie van optisch actief 3-careen racemisch3,7,7-trimethyl-bicyclo[4.1.0] 3-hepteen-2,5-dion zou ontstaan is onvol­doende gemotiveerd.(A. Zabza & H. Kuczynski, Roczniki Chem., 40, 433 (1966)).

3/ Oxydatie van cis-g-decalon-hydrazon met HgO is wellicht de eenvoudigstemanier om twistaan te synthetiseren.

4/ Schaefer en Horvath hebben over het hoofd gezien, dat het mogelijk ishet voorkomen van een 1,3-diaryl-propenyl-carbonium ion, dat door henwerd voorgesteld als intermediair bij de oxydatie met selenium dioxidevan 1,3-diaryl-propenen, te bewijzen door een combinatie van experimenten P.P.P.-berekeningen.(J.P. Schaefer & B. Horvath, Tetrahedron Letters, (1964) (30) 2023).

5/ De experimentele resultaten van Volpi en Pietra betreffende deTiffBneau-Demjanov-ringverwijding van norcamfer zijn zó onvolledig, datpublicatie beter achterwege had kunnen blijven.(E. Volpi & F. Pietra, Tetrahedron Letters, (1972) (40) 4067).

6/ Het is aanbevelenswaardig in het leerplan kunstgeschiedenis ook achter­gronden en toepassingen op te nemen van fysischs en chemische methodenom de autenticiteit van kunstvoorwerpen vast te stellen.

7/ Hsia, Shang en Chou bronzen zijn geen goede geldbelegging.

6/ Het kan aanleiding geven tot maatschappelijke onrechtvaardigheid, datstrafrechtelijk beter kan worden opgetreden tegen iemand, die een diermishandelt, dan tegen iemand, die een mens mishandelt.

9/ De bemoeienis van hst R.I.B. met de aankoop van chemicaliën, die niettot de standaard magazijnvoorraad van een rijksoverheidslaboratoriumbehoren, werkt remmend op het wetenschappelijk onderzoek en belangrijkkostenverhogend.

W.C.M.C. Kokke 29 maart 1973.

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